GLAc.937G>TLikely benign

Print report

Variant interpretation report

GLA c.937G>T, p.(Asp313Tyr)

NM_000169.3:c.937G>T NP_000160.1:p.(Asp313Tyr) View identifiers

Classification

Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About GLA

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (benign) · 4 supporting (benign)
Expert rules: Not recorded
Other laboratories (ClinVar): 10 Benign · 7 Likely benign · 4 Uncertain significance · 2 other
Pipeline record: 1 Jul 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

BS1 (supporting): This variant is present in gnomAD at an allele frequency of 0.304% (v2.1, 624/205,260 alleles, 3 homozygotes) and 0.378% (v4.1, 4,565/1,207,947 alleles, 10 homozygotes), with a grpmax filtering allele frequency of 0.405%. These frequencies exceed the non-VCEP BS1 threshold of >0.3%, supporting a benign interpretation for a fully penetrant X-linked disorder.
BS2 (supporting): This variant is observed in homozygous state in gnomAD: 3 homozygotes in v2.1 and 10 homozygotes in v4.1. Fabry disease is an X-linked disorder with full penetrance in hemizygous males. The presence of multiple homozygous individuals in a population database that screens out severe pediatric disease indicates this variant is observed in healthy adults and does not cause Fabry disease.
BS3 (strong): Well-established functional studies demonstrate that D313Y is a pseudodeficiency allele, not a pathogenic variant. In COS-7 cells, D313Y retains approximately 60% of wild-type alpha-galactosidase A enzymatic activity, localizes properly to lysosomes, and is stable at lysosomal pH (4.6). The D313Y enzyme is not evolutionarily conserved and the substitution is structurally tolerated. Lyso-Gb3 biomarker levels are normal in D313Y carriers, confirming absence of glycolipid accumulation. D313Y was found in 0.45% of normal X-chromosomes in a control population.
BP4 (supporting): Multiple in silico predictors support a benign interpretation. SpliceAI predicts no splicing impact (max delta score = 0.00), indicating the nucleotide change does not create or disrupt splice sites. BayesDel score of 0.065 is in the benign range (below ~0.13 damaging threshold). While REVEL is unavailable, the concordance of available predictors supports a benign computational profile.
BP6 (supporting): ClinVar classifies this variant as Benign based on submissions from 10 clinical laboratories, with an additional 7 laboratories reporting Likely benign. Only 4 laboratories report Uncertain significance, and 2 report other. The majority consensus among clinical laboratories strongly supports a benign interpretation.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 5

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 5

BS1Supporting

BS1 · supporting

This variant is present in gnomAD at an allele frequency of 0.304% (v2.1, 624/205,260 alleles, 3 homozygotes) and 0.378% (v4.1, 4,565/1,207,947 alleles, 10 homozygotes), with a grpmax filtering allele frequency of 0.405%. These frequencies exceed the non-VCEP BS1 threshold of >0.3%, supporting a benign interpretation for a fully penetrant X-linked disorder.

BS2Supporting

BS2 · supporting

This variant is observed in homozygous state in gnomAD: 3 homozygotes in v2.1 and 10 homozygotes in v4.1. Fabry disease is an X-linked disorder with full penetrance in hemizygous males. The presence of multiple homozygous individuals in a population database that screens out severe pediatric disease indicates this variant is observed in healthy adults and does not cause Fabry disease.

BS3Strong

BS3 · strong

Well-established functional studies demonstrate that D313Y is a pseudodeficiency allele, not a pathogenic variant. In COS-7 cells, D313Y retains approximately 60% of wild-type alpha-galactosidase A enzymatic activity, localizes properly to lysosomes, and is stable at lysosomal pH (4.6). The D313Y enzyme is not evolutionarily conserved and the substitution is structurally tolerated. Lyso-Gb3 biomarker levels are normal in D313Y carriers, confirming absence of glycolipid accumulation. D313Y was found in 0.45% of normal X-chromosomes in a control population.

BP4Supporting

BP4 · supporting

Multiple in silico predictors support a benign interpretation. SpliceAI predicts no splicing impact (max delta score = 0.00), indicating the nucleotide change does not create or disrupt splice sites. BayesDel score of 0.065 is in the benign range (below ~0.13 damaging threshold). While REVEL is unavailable, the concordance of available predictors supports a benign computational profile.

BP6Supporting

BP6 · supporting

ClinVar classifies this variant as Benign based on submissions from 10 clinical laboratories, with an additional 7 laboratories reporting Likely benign. Only 4 laboratories report Uncertain significance, and 2 report other. The majority consensus among clinical laboratories strongly supports a benign interpretation.

Recorded classification: Likely benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 supporting, BS2 supporting, BS3 strong, BP4 supporting, BP6 supporting; combination = 1 strong benign + 4 supporting benign, which maps to Likely Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

4,565 / 1,207,947 alleles

gnomAD v4.1: 4,565 / 1,207,947 alleles. Recorded AF 0.00377914. Recorded homozygote count 10.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00304005; MAF= 0.30400%, 624/205260 alleles, homozygotes = 3) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00691545; MAF= 0.69154%, 53/7664 alleles, homozygotes = 0); grpmax FAF= 0.0040545.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0029704338214976513, 43/14476 alleles, homozygotes = 1).

Applied · BS1, BS2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗

ClinVar submissions

23 reported laboratory submissions

10 Benign · 7 Likely benign · 4 Uncertain significance · 2 other.

Applied · BP6 → ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

Applied · BS3 → OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV54510729, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 5 met · 8 not met · 9 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000169.3:c.937G>T (p.Asp313Tyr) is a missense variant in exon 6 of GLA observed at high frequency in population databases: 0.304% in gnomAD v2.1 (624/205,260 alleles, 3 homozygotes) and 0.378% in gnomAD v4.1 (4,565/1,207,947 alleles, 10 homozygotes).

Well-established functional studies demonstrate D313Y is a pseudodeficiency allele retaining approximately 60% of wild-type alpha-galactosidase A activity with proper lysosomal localization. The enzyme is stable at lysosomal pH, and Lyso-Gb3 biomarker levels are normal in D313Y carriers.

ClinVar reports this variant as Benign by 10 clinical laboratories and Likely benign by 7, with only 4 reporting Uncertain significance and 2 reporting other. The majority consensus supports a benign interpretation.

Multiple in silico predictors support a benign interpretation: SpliceAI predicts no splicing impact (max delta = 0.00), and BayesDel score of 0.065 is in the benign range.

Based on the generic ACMG/AMP 2015 framework, the combined evidence includes BS1 (supporting benign), BS2 (supporting benign), BS3 (strong benign), BP4 (supporting benign), and BP6 (supporting benign). No pathogenic criteria are met. The overall classification is Benign.

Met · 5

BS1 SupportingThis variant is present in gnomAD at an allele frequency of 0.304% (v2.1, 624/205,260 alleles, 3 homozygotes) and 0.378% (v4.1, 4,565/1,207,947 alleles, 10 homozygotes), with a grpmax filtering allele frequency of 0.405%. These frequencies exceed the non-VCEP BS1 threshold of >0.3%, supporting a benign interpretation for a fully penetrant X-linked disorder. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=0.304%
624/205
260 alleles
3 homozygotes
gnomAD v4.1: AF=0.378%
4
565/1
207
947 alleles
10 homozygotes
grpmax FAF=0.405% (v2.1)
0.426% (v4.1)
Presence of homozygotes in a population database excluding severe pediatric disease

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 SupportingThis variant is observed in homozygous state in gnomAD: 3 homozygotes in v2.1 and 10 homozygotes in v4.1. Fabry disease is an X-linked disorder with full penetrance in hemizygous males. The presence of multiple homozygous individuals in a population database that screens out severe pediatric disease indicates this variant is observed in healthy adults and does not cause Fabry disease. Details ▾Hide ▴

Evidence considered

3 homozygotes in gnomAD v2.1
10 homozygotes in gnomAD v4.1
gnomAD excludes individuals with severe pediatric disease

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 StrongWell-established functional studies demonstrate that D313Y is a pseudodeficiency allele, not a pathogenic variant. In COS-7 cells, D313Y retains approximately 60% of wild-type alpha-galactosidase A enzymatic activity, localizes properly to lysosomes, and is stable at lysosomal pH (4.6). The D313Y enzyme is not evolutionarily conserved and the substitution is structurally tolerated. Lyso-Gb3 biomarker levels are normal in D313Y carriers, confirming absence of glycolipid accumulation. D313Y was found in 0.45% of normal X-chromosomes in a control population. Details ▾Hide ▴

Evidence considered

~60% WT enzymatic activity in COS-7 cells with proper lysosomal localization (PMID:14635108)
D313Y enzyme stable at lysosomal pH 4.6
reduced activity only at neutral pH (PMID:14635108)
Normal Lyso-Gb3 levels in D313Y carriers — no glycolipid accumulation (PMID:23430502)
D313Y found in 0.45% of normal X-chromosomes in Caucasian controls (PMID:14635108)
Structural model shows D313Y is tolerated
Asp313 is not conserved (PMID:14635108)

Sources

PMID:14635108 ↗PMID:23430502 ↗

BP4 SupportingMultiple in silico predictors support a benign interpretation. SpliceAI predicts no splicing impact (max delta score = 0.00), indicating the nucleotide change does not create or disrupt splice sites. BayesDel score of 0.065 is in the benign range (below ~0.13 damaging threshold). While REVEL is unavailable, the concordance of available predictors supports a benign computational profile. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 — no predicted splice impact
BayesDel = 0.065 — benign range

Still missing

REVEL score unavailable for chrX

Sources

spliceai ↗bayesdel

BP6 SupportingClinVar classifies this variant as Benign based on submissions from 10 clinical laboratories, with an additional 7 laboratories reporting Likely benign. Only 4 laboratories report Uncertain significance, and 2 report other. The majority consensus among clinical laboratories strongly supports a benign interpretation. Details ▾Hide ▴

Evidence considered

ClinVar classification: Benign (10 clinical labs)
Likely benign (7 clinical labs)
Uncertain significance (4 labs)
Other (2 labs)
ClinVar Variation ID: 10738

Sources

clinvar ↗

Not met · 8 · evaluated, threshold not reached

PS3 Functional studies in COS-7 cells demonstrate that D313Y retains approximately 60% of wild-type alpha-galactosidase A enzymatic activity with proper lysosomal localization; the enzyme is stable at lysosomal pH (4.6) but shows reduced activity at neutral pH (7.4). This is consistent with a hypomorphic/pseudodeficiency allele, not a complete loss of function. The Lyso-Gb3 biomarker data confirms D313Y is not clinically relevant for Fabry disease. Details ▾Hide ▴

Evidence considered

COS-7 expression: ~60% WT enzymatic activity
normal lysosomal localization (PMID:14635108)
Lyso-Gb3 levels normal in D313Y carriers
indicating no glycolipid accumulation (PMID:23430502)
D313Y found in 0.45% of normal X-chromosomes (PMID:14635108)

Sources

PMID:14635108 ↗PMID:23430502 ↗

PM1 Residue Asp313 is located in an alpha-helix on the perimeter of the beta/alpha-barrel domain, distant from the active site and dimer interface. The residue is not evolutionarily conserved (Asp-313 occurs in only one mammalian alpha-Gal A ortholog). No mutational hotspot or critical functional domain was identified at this position. The variant does not lie in a statistically significant hotspot. Details ▾Hide ▴

Evidence considered

Asp313 is solvent-exposed
in a peripheral alpha-helix
not in the active site (PMID:14635108)
Residue is poorly conserved across species (PMID:14635108)
Not in a statistically significant hotspot

Sources

PMID:14635108 ↗

PM2 This variant is present in gnomAD at a frequency of 0.304% (v2.1: 624/205,260 alleles) and 0.378% (v4.1: 4,565/1,207,947 alleles). Under the non-VCEP threshold of <0.1% for PM2, this frequency substantially exceeds the cutoff; PM2 is not met. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=0.304%
624/205
260 alleles
3 homozygotes
gnomAD v4.1: AF=0.378%
4
565/1
207
947 alleles
10 homozygotes

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP2 GLA has numerous benign missense variants documented in population databases including D313Y itself. PP2 requires a gene where missense variants are a common disease mechanism and benign missense variation is low, which does not apply to GLA given the high frequency of benign missense variants observed. Details ▾Hide ▴

Evidence considered

D313Y itself is a common benign missense variant in GLA at 0.3-0.4% frequency

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP3 In silico predictions are consistent with a benign interpretation. SpliceAI predicts no splicing impact (max delta score = 0.00). BayesDel score is 0.065, well below the typical damaging threshold of ~0.13. REVEL score is unavailable. No computational evidence supports a deleterious effect. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no splicing impact)
BayesDel = 0.065 (benign range
below ~0.13 threshold)

Still missing

REVEL score unavailable for chrX

Sources

spliceai ↗bayesdel

PP5 ClinVar reports this variant as Benign (10 clinical laboratories), Likely benign (7), and Uncertain significance (4). The majority classification is benign. PP5 requires a reputable source to report the variant as pathogenic, which is not the case here. Details ▾Hide ▴

Evidence considered

ClinVar classification: Benign (10 labs)
Likely benign (7 labs)
VUS (4 labs)

Sources

clinvar ↗

BA1 The variant frequency in gnomAD is 0.304% (v2.1) and 0.378% (v4.1), which is below the BA1 threshold of >1% allele frequency. While common, the frequency does not reach the stand-alone benign threshold. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=0.304% (below 1% BA1 threshold)
gnomAD v4.1: AF=0.378% (below 1% BA1 threshold)

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP5 This variant has been extensively reported in the literature in association with Fabry disease, stroke, white matter lesions, and other phenotypes. It does not meet the BP5 criterion which requires the variant to be found in a case with an alternate molecular cause for disease. No such alternate cause was identified in the reviewed cases. Details ▾Hide ▴

Evidence considered

Variant observed in multiple disease-associated cohorts
no alternate molecular cause documented

Not assessed · 9 · no assessment recorded

PS1 No pathogenic substitution at the same nucleotide position (c.937) was identified. PS1 requires a known pathogenic variant at the same nucleotide position with a different amino acid change; no such comparator exists in ClinVar or the literature for this residue. Details ▾Hide ▴

Evidence considered

No known pathogenic alternate change at c.937

Still missing

No same-position pathogenic variant available for comparison

PS2 No de novo data were identified in any of the reviewed publications or ClinVar submissions for this variant. Details ▾Hide ▴

Evidence considered

No de novo reports found

Still missing

No de novo testing data available

PS4 No case-control study with adequate statistical power comparing variant prevalence in Fabry disease cases versus controls was identified. The variant is common in population databases (0.3-0.4%), which would confound any case-control comparison. Details ▾Hide ▴

Evidence considered

Variant present at 0.304% in gnomAD v2.1 — too common for case-control enrichment

Still missing

No formal case-control study available

PM6 Not applicable — skipped per instruction. Details ▾Hide ▴

No further detail was recorded.

PP1 While PMID:23393592 reports family screening data for D313Y carriers with white matter lesions, the segregation data are insufficient to meet PP1 thresholds. The variant is too common in the general population to assess meaningful cosegregation without formal LOD scores. Details ▾Hide ▴

Evidence considered

Family screening reported in PMID:23393592 but insufficient for formal cosegregation analysis

Still missing

No formal segregation analysis with LOD scores

PP4 The variant has been observed in patients with diverse phenotypes (stroke, white matter lesions, cardiomyopathy, renal disease), but also in healthy controls at high population frequency. Phenotype specificity is insufficient to support PP4. Details ▾Hide ▴

Evidence considered

D313Y found in stroke patients (PORTYSTROKE) and WML patients
but also at 0.3-0.4% in population controls

Still missing

Phenotype is not specific to Fabry disease in reported carriers

Sources

PMID:20110537 ↗PMID:23393592 ↗

BS4 No formal cosegregation studies with LOD scores were identified. Given the high population frequency of D313Y, meaningful cosegregation analysis is challenging. Details ▾Hide ▴

Evidence considered

No formal segregation analysis available

Still missing

No segregation data with adequate statistical power

BP2 No observation of this variant in trans with a known pathogenic GLA variant was identified in the reviewed literature. Given Fabry disease is X-linked, BP2 is less applicable but could be considered if observed in trans in a female. Details ▾Hide ▴

Evidence considered

No in trans observation with a pathogenic variant documented

Still missing

No in trans data available

PS5 Not applicable — skipped per instruction. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense variant (c.937G>T, p.Asp313Tyr). The generic PVS1 framework (PMC6185798) only applies to null variants: nonsense, frameshift, or canonical ±1,2 splice consensus variants. Missense substitutions are outside the PVS1 decision tree scope. Details ▾Hide ▴

Evidence considered

Exon 6 missense substitution
not a null variant

Sources

pvs1_generic_framework ↗

PM5 N/ANo same-residue comparator variants with confirmed pathogenicity were identified in ClinVar; automatic candidate harvesting was unable to confirm classic same-residue PM5 semantics. Details ▾Hide ▴

Evidence considered

No same-residue pathogenic comparators found

BP1 N/AThis is a missense variant. BP1 applies only when a truncating variant in a gene where loss of function is the known disease mechanism would be expected to be pathogenic, but is observed as benign. D313Y is not a truncating variant. Details ▾Hide ▴

Evidence considered

Missense substitution
not a truncating variant

BP3 N/ASkipped — trivially not applicable (in-frame indels in repetitive regions). Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (c.937G>T, p.Asp313Tyr). BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense substitution
not a synonymous variant

Identifiers

Gene: GLA
Transcript: NM_000169.3
Coding (HGVS c.): NM_000169.3:c.937G>T
Protein (HGVS p.): NP_000160.1:p.(Asp313Tyr)
GRCh38: chrX:101398432 C>A
GRCh37: chrX:100653420 C>A
ClinVar: 10738
COSMIC: COSV54510729

Gene diagram

Every interpreted variant in GLA, mapped onto the exon structure of NM_000169.3. Select a row to find it on the plot.

GLANM_000169.3

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in GLA — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 4,565 / 1,207,947 alleles AF 0.00378 · 10 homozygotes · FAF 0.00426

gnomAD v2.1 624 / 205,260 alleles AF 0.00304 · 3 homozygotes · FAF 0.00405

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.0038 · 4565 / 1,207,947 alleles · 10 hom · FAF 0.0043

Ashkenazi Jewish138 / 22,020	0.00631 hom
European (non-Finnish)3912 / 893,709	0.00445 hom
Middle Eastern18 / 4,329	0.0042
Remaining individuals157 / 47,550	0.00331 hom
South Asian183 / 56,710	0.00322 hom
Admixed American88 / 45,679	0.00191 hom
European (Finnish)35 / 46,477	0.00075
African/African American34 / 57,057	0.0006

0 alternate alleles recorded in 2 other groups: Amish, East Asian.

gnomAD v2.1

AF 0.003 · 624 / 205,260 alleles · 3 hom · FAF 0.0041

Ashkenazi Jewish53 / 7,664	0.0069
European (non-Finnish)413 / 92,674	0.00451 hom
Remaining individuals22 / 5,331	0.0041
South Asian48 / 19,080	0.0025
Admixed American58 / 28,054	0.00211 hom
European (Finnish)16 / 18,615	0.000861 hom
African/African American14 / 19,000	0.00074

0 alternate alleles recorded in 1 other group: East Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00377914; MAF= 0.37791%, 4565/1207947 alleles, homozygotes = 10) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00626703; MAF= 0.62670%, 138/22020 alleles, homozygotes = 1); grpmax FAF= 0.0042627.

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0029704338214976513, 43/14476 alleles, homozygotes = 1).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -498 bp

0.000

SpliceAI acceptor gainat +24 bp

0.000

SpliceAI donor lossat -361 bp

0.000

SpliceAI donor gainat -418 bp

0.000

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: 0.065

How the predictions were used

Evidence considered

SpliceAI max delta = 0.00 — no predicted splice impact
BayesDel = 0.065 — benign range

Still missing

REVEL score unavailable for chrX

Sources

spliceai ↗bayesdel

Evidence considered

SpliceAI max delta = 0.00 (no splicing impact)
BayesDel = 0.065 (benign range
below ~0.13 threshold)

Still missing

REVEL score unavailable for chrX

Sources

spliceai ↗bayesdel

BP7 N/AThis is a missense variant (c.937G>T, p.Asp313Tyr). BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense substitution
not a synonymous variant

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.0650709.

8 paper records listed. 2 cited in the classification.

Cited in the classification

Fabry disease: characterization of alpha-galactosidase A double mutations and the D313Y plasma enzyme pseudodeficiency allele.

Yasuda M et al. · 2003 Dec

D313Y was characterized as a pseudodeficiency allele. Expressed D313Y retained ~60% WT enzymatic activity in COS-7 cells, localized properly to lysosomes, and was stable at lysosomal pH 4.6 but showed reduced activity at neutral pH 7.4. D313Y occurred in 0.45% of 883 normal X-chromosomes. The D313Y substitution is structurally tolerated: Asp313 is solvent-exposed in a peripheral alpha-helix, not conserved in evolution, and the tyrosine substitution is easily accommodated. The authors conclude D313Y is a rare coding sequence variant causing pseudodeficiency in plasma.
→ BS3 Names this variant
PMID 14635108 ↗
Source detail

Thus, D313Y is a rare exonic variant with about 60% of wild-type activity in vitro and reduced activity at neutral pH, resulting in low plasma a-Gal A activity.

Location Abstract; Results (Mutation Detection and Frequency, Expression Studies, pH Stability); Discussion; Figure 1-4

Context COS-7 cell transient transfection; alpha-galactosidase A fluorogenic enzyme assay; immunofluorescence microscopy with LAMP-2 (lysosomal) and BiP (ER) markers; pH stability assay; molecular homology modeling based on chicken alpha-Gal B crystal structure
Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease.

Lyso-Gb3 biomarker analysis in D313Y carriers demonstrated normal levels, indicating absence of glycolipid accumulation characteristic of Fabry disease. The authors conclude that D313Y is not clinically relevant for Fabry disease and that reduced alpha-galactosidase A activity in plasma represents a pseudodeficiency rather than true enzyme deficiency.
→ BS3 Names this variant
PMID 23430502 ↗
Source detail

Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease.

Location Abstract; Results; Discussion

Other recorded publications

Fabry disease: 20 novel GLA mutations in 35 families.

Blaydon D et al. · 2001

D313Y (c.937G>T, p.Asp313Tyr) is listed in a mutation table as a previously reported GLA missense mutation found in a female patient with acroparaesthesias. The authors note D313Y is not in a conserved residue and predict it causes disease based on charge change, but no functional data are provided.
Names this variant
PMID 11668641 ↗
Quoted passage
All of the missense mutations, except for D313Y and R363H, occur in highly conserved residues of the α-galactosidase A amino acid sequence.
Table 1, Discussion paragraph 3
[Ophthalmological manifestations in Fabry's disease. Four clinical cases showing deficient alpha-galactosidase-A activity].

Three patients (p2, p3, p4) from two families carried the Asp313Tyr mutation in exon 6. One was an 81-year-old male with Fabry disease and hypertrophic cardiomyopathy who showed no ocular signs of Fabry; a 45-year-old healthy male carrier showed conjunctival vascular abnormalities and corneal opacities; a 56-year-old male with Fabry and HCM showed corneal verticillata and conjunctival vascular ectasias. The authors note that ophthalmological involvement is inconsistent — some Fabry patients have no ocular findings and some healthy carriers have characteristic findings.
Names this variant
PMID 19085643 ↗
Quoted passage
tres pacientes (p2, p3, p4) presentaron una alteración en el exón 6 (Asp313Tyr)
Case Reports (Casos Clínicos), Cases 2-4
Mutations of the GLA gene in young patients with stroke: the PORTYSTROKE study--screening genetic conditions in Portuguese young stroke patients.

In the PORTYSTROKE study screening 493 young stroke patients in Portugal, 6 patients carried the p.D313Y mutation: 5 with ischemic stroke (3 males, 2 females) and 1 male with intracerebral hemorrhage. Leukocyte alpha-galactosidase activity was subnormal in hemizygous males and subnormal to low-normal in heterozygous females. The D313Y allele was not found in over 400 X chromosomes of healthy Portuguese controls. The authors note that D313Y's pathogenic role has been challenged and it may be a low-frequency polymorphism.
Names this variant
PMID 20110537 ↗
Quoted passage
Mutation p.D313Y was first described in a patient with the classical FD phenotype, but its pathogenic role has been subsequently challenged.
Results (paragraphs 1-4); Discussion (paragraphs 3-6)
Frequency of Fabry disease in male and female haemodialysis patients in Spain.

This paper reports a screening study of Fabry disease in hemodialysis patients in Spain using combined enzymatic and genetic testing. NM_000169.3:c.937G>T (p.D313Y) was not identified in this paper.
Does not name this variant
PMID 20122163 ↗
Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young.

In the Belgian Fabry Study (BeFaS) of 1,000 young patients with stroke or unexplained white matter lesions, the p.D313Y mutation was identified in female patients. Upon family screening and phenotyping, all p.D313Y carriers had normal alpha-galactosidase A enzyme activity in plasma and normal Gb3 and lyso-Gb3 values. All had normal renal function. Four index patients had cerebral white matter lesions and one female had mild cardiac septal hypertrophy. The authors cite prior work establishing D313Y as a pseudodeficiency allele.
Names this variant
PMID 23219219 ↗
Quoted passage
All p.D313Y mutation carriers had a normal renal function.
Abstract; Results (paragraphs on BeFaS mutation findings); Discussion
Multifocal white matter lesions associated with the D313Y mutation of the α-galactosidase A gene.

Lenders M et al. · 2013

This study examined 5 patients (3 female, 2 male) carrying the D313Y mutation who presented with multifocal white matter lesions. Family screening identified 14 additional D313Y carriers. Alpha-galactosidase A activity was decreased in plasma but normal or mildly reduced in leukocytes. Lyso-Gb3 levels were normal in all carriers. The authors propose D313Y may confer increased risk for white matter lesions through a gain-of-function or modifier effect rather than classic Fabry disease pathophysiology, since no glycolipid accumulation was detected.
Names this variant
PMID 23393592 ↗
Quoted passage
Multifocal white matter lesions associated with the D313Y mutation of the α-galactosidase A gene.
Abstract; Results; Discussion

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 4,565 / 1,207,947 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 10 Benign · 7 Likely benign · 4 Uncertain significance · 2 other Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0029704338214976513, 43/14476 alleles, homozygotes = 1).

ClinVar

This variant has been reported in ClinVar as Benign (10 clinical laboratories) and as Likely benign (7 clinical laboratories) and as Uncertain significance (4 clinical laboratories) and as other (2 clinical laboratories). (ClinVarID = 10738)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.0650709.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54510729, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.