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SDHDc.110A>TUncertain significance
Print report
Variant interpretation report

SDHD c.110A>T, p.(Asp37Val)

NM_003002.4:c.110A>T NP_002993.1:p.(Asp37Val) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About SDHD

No gene-level summary was recorded for this case.

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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

NM_003002.4:c.110A>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with allele frequency well below the 0.1% threshold for PM2 under the generic ACMG framework.

PP3Supporting
PP3 · supporting

Multiple in silico tools support a deleterious effect. REVEL score of 0.701 exceeds the typical 0.5 threshold for pathogenicity prediction. SpliceAI predicts a possible splice alteration with a maximum delta score of 0.30 (DS_AL=0.30, DS_DL=0.27). BayesDel score of 0.257 is not independently supportive but does not contradict.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.

02The sources

Evidence at a glance

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

SpliceAI score
0.300 maximum delta

Recorded SpliceAI maximum delta score: 0.300. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

1 Uncertain significance · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SDHD, a subunit of succinate dehydrogenase, is infrequently altered in cancer.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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.

29 criteria with recorded statuses: 2 met · 12 not met · 9 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_003002.4:c.110A>T (p.Asp37Val) in SDHD is absent from all gnomAD population databases (v2.1, v4.1, gnomAD-Canada), supporting PM2 at supporting strength.

In silico predictions support a deleterious effect: REVEL score 0.701 and SpliceAI max delta 0.30 suggest possible functional and splice impact, meeting PP3 at supporting strength.

No variant-specific functional studies, case reports, segregation data, or expert panel classifications are available. ClinVar contains two single-submitter classifications (Uncertain significance, Likely pathogenic), neither from an expert panel.

With only PM2 (supporting) and PP3 (supporting) met, the evidence is insufficient to classify this variant as pathogenic or likely pathogenic under the generic ACMG/AMP 2015 framework. The variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingNM_003002.4:c.110A>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with allele frequency well below the 0.1% threshold for PM2 under the generic ACMG framework. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD population databases (v2.1 exomes
  • v4.1 exomes
  • gnomAD-Canada genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingMultiple in silico tools support a deleterious effect. REVEL score of 0.701 exceeds the typical 0.5 threshold for pathogenicity prediction. SpliceAI predicts a possible splice alteration with a maximum delta score of 0.30 (DS_AL=0.30, DS_DL=0.27). BayesDel score of 0.257 is not independently supportive but does not contradict. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.701 (deleterious).
  • SpliceAI max delta: 0.30 (possible splice alteration
  • acceptor loss 0.30
  • donor loss 0.27).
Still missing
  • BayesDel score 0.257 is below typical pathogenicity threshold
  • in silico consensus is not unanimous.
Sources
revelspliceai ↗bayesdel

Not met · 12 · evaluated, threshold not reached

PS1 No evidence that the same amino acid change (p.Asp37Val) arising from a different nucleotide substitution has been previously established as pathogenic. No ClinVar entries or literature reports identify a different nucleotide change producing the same Asp37Val substitution. Details ▾Hide ▴
Evidence considered
  • ClinVar variation 940748 contains only the c.110A>T nucleotide change
  • no alternative nucleotide changes producing p.Asp37Val were identified.
Still missing
  • No systematic search for alternative nucleotide changes at codon 37 producing p.Asp37Val.
Sources
clinvar ↗
PS3 No variant-specific functional studies were identified for NM_003002.4:c.110A>T (p.Asp37Val). OncoKB records this variant as having unknown oncogenic effect. No publications with experimental functional characterization of this exact variant or a systematically characterized range encompassing position 37 were found. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect. No functional publications found.
Still missing
  • No functional assays performed on this variant.
  • No systematic functional characterization of the N-terminal region of SDHD available in the case materials.
Sources
oncokb ↗
PS4 No case reports or patient observations documenting this specific variant were identified in the literature. The ClinVar-associated PMIDs are clinical practice guidelines and review articles that do not mention NM_003002.4:c.110A>T. Details ▾Hide ▴
Evidence considered
  • Variant is present in ClinVar (940748) from two clinical laboratories but without accompanying published case reports.
Still missing
  • No published cases documenting phenotype associated with this variant.
Sources
clinvar ↗
PM1 Position 37 of SDHD is not within a statistically significant mutational hotspot per cancerhotspots.org, and no literature evidence in the case materials establishes this N-terminal region as a well-characterized critical functional domain with demonstrated variant-level impact at this residue. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: residue not in a statistically significant hotspot.
  • No domain-level functional characterization of the SDHD N-terminal region at residue 37 identified in the literature reviewed.
Still missing
  • Comprehensive domain annotation of SDHD residue 37 not performed.
  • May warrant review if the mitochondrial targeting signal includes residue 37.
Sources
oncokb ↗
PM5 No pathogenic missense comparators at the same residue (position 37) with a different amino acid change were identified. The automated PM5 candidate search returned zero candidates. Details ▾Hide ▴
Evidence considered
  • Zero same-residue comparator candidates found in ClinVar at position 37.
Sources
pm5_candidates
PP2 No gene-specific missense constraint metric is available for SDHD. The HCI prior was not found for this gene, and no custom PP2 score exists. Without statistical evidence that SDHD has a low rate of benign missense variation, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for SDHD.
Still missing
  • Gene-specific missense constraint data (e.g.
  • missense Z-score
  • LOEUF) not computed for SDHD.
PP5 ClinVar review status for variation 940748 is 'criteria provided, single submitter' — not a 3-star expert panel classification. Under the PP5 rule requiring a 3-star expert panel assertion of pathogenicity, this does not qualify. The two submissions are VUS (Invitae) and Likely Pathogenic (Ambry Genetics), neither from an expert panel. Details ▾Hide ▴
Evidence considered
  • ClinVar variation 940748: review status 'criteria provided
  • single submitter'
  • no expert panel classification.
Sources
clinvar ↗
BA1 The variant is absent from all gnomAD population databases. Allele frequency does not exceed the 1% threshold required for BA1. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada
  • allele frequency 0.0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from all gnomAD population databases. Allele frequency does not exceed the 0.3% threshold required for BS1. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada
  • allele frequency 0.0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP1 Although SDHD is a tumor suppressor gene where loss-of-function is the primary disease mechanism, pathogenic missense variants in SDHD are well-established in hereditary paraganglioma-pheochromocytoma syndromes. BP1 is intended for genes where only truncating variants cause disease, which does not apply to SDHD. Details ▾Hide ▴
Evidence considered
  • SDHD pathogenic variants include both truncating and missense alterations
  • missense variants are a recognized disease mechanism in hereditary PPGL syndromes.
BP4 Multiple in silico tools predict a deleterious rather than benign effect. REVEL score of 0.701 supports pathogenicity and SpliceAI max delta of 0.30 suggests possible splice alteration. These predictions do not support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL 0.701 (not benign).
  • SpliceAI max delta 0.30 (possible splice impact).
Sources
revelspliceai ↗bayesdel
BP6 No expert panel has classified this variant as benign or likely benign. ClinVar review status is 'criteria provided, single submitter' with submissions of VUS and Likely Pathogenic — neither constitutes a 3-star expert panel benign assertion. Details ▾Hide ▴
Evidence considered
  • ClinVar variation 940748: no expert panel benign classification available.
Sources
clinvar ↗

Not assessed · 9 · no assessment recorded

PS2 No de novo testing data available. No report of this variant confirmed as de novo in any publication or clinical database. Details ▾Hide ▴
Still missing
  • No parental testing data available.
PM6 No de novo confirmation data available for this variant. No publication or clinical report documents NM_003002.4:c.110A>T as a confirmed de novo event. Details ▾Hide ▴
Still missing
  • No parental testing data available.
PP1 No segregation data available. No family studies or co-segregation analysis has been performed for this variant. Details ▾Hide ▴
Still missing
  • No family members tested for this variant.
PP4 Patient phenotype information was not provided in the case materials. Phenotype specificity for hereditary paraganglioma-pheochromocytoma syndrome cannot be evaluated without clinical data. Details ▾Hide ▴
Still missing
  • Patient phenotype not available for review.
BS2 No data on observation of this variant in healthy adult controls is available. The variant is absent from population databases, so the question of observation in healthy individuals is moot. Details ▾Hide ▴
Still missing
  • No control cohort data available.
BS3 No functional studies demonstrating no damaging effect on protein function or splicing are available for this variant. Details ▾Hide ▴
Still missing
  • No functional assays have been performed on this variant.
BS4 No segregation data available to evaluate lack of co-segregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data available.
BP2 No data on observation of this variant in trans with a known pathogenic variant in SDHD. Details ▾Hide ▴
Still missing
  • No phase data available.
BP5 No evidence of an alternate molecular basis for disease in a case where this variant was observed. Details ▾Hide ▴
Still missing
  • No alternate genetic etiology data available.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. NM_003002.4:c.110A>T (p.Asp37Val) does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution (p.Asp37Val)
  • not a predicted null variant.
Sources
pvs1_generic_framework ↗
PM3 N/APM3 requires observation in trans with a pathogenic variant for recessive disorders; SDHD-associated disease follows autosomal dominant inheritance with paternal parent-of-origin effects, making PM3 inapplicable. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss); NM_003002.4:c.110A>T is a missense substitution with no protein length change. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; NM_003002.4:c.110A>T is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants without predicted splice effect. NM_003002.4:c.110A>T is a missense variant (p.Asp37Val), not a synonymous substitution. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.
PS5 N/APS5 is not a criterion defined in the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868). The standard ACMG criteria do not include PS5. Details ▾Hide ▴
Evidence considered
  • PS5 does not exist in the generic ACMG/AMP framework.
Sources
generic_acmg_combination_rules

Identifiers

Gene
SDHD
Transcript
NM_003002.4
Coding (HGVS c.)
NM_003002.4:c.110A>T
Protein (HGVS p.)
NP_002993.1:p.(Asp37Val)
GRCh38
chr11:112087914 A>T
GRCh37
chr11:111958638 A>T
ClinVar
940748

Gene diagram

Every interpreted variant in SDHD, mapped onto the exon structure of NM_003002.4. Select a row to find it on the plot.

SDHDNM_003002.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -57 bp
0.300
SpliceAI acceptor gainat -1 bp
0.000
SpliceAI donor lossat +59 bp
0.270
SpliceAI donor gainat -2 bp
0.030
Pangolin splice lossmagnitude shown
-0.290
Pangolin splice gain
0.060

Other predictors

REVEL
0.701
BayesDel
0.257

How the predictions were used

PP3 SupportingMultiple in silico tools support a deleterious effect. REVEL score of 0.701 exceeds the typical 0.5 threshold for pathogenicity prediction. SpliceAI predicts a possible splice alteration with a maximum delta score of 0.30 (DS_AL=0.30, DS_DL=0.27). BayesDel score of 0.257 is not independently supportive but does not contradict. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.701 (deleterious).
  • SpliceAI max delta: 0.30 (possible splice alteration
  • acceptor loss 0.30
  • donor loss 0.27).
Still missing
  • BayesDel score 0.257 is below typical pathogenicity threshold
  • in silico consensus is not unanimous.
Sources
revelspliceai ↗bayesdel
BP4 Multiple in silico tools predict a deleterious rather than benign effect. REVEL score of 0.701 supports pathogenicity and SpliceAI max delta of 0.30 suggests possible splice alteration. These predictions do not support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL 0.701 (not benign).
  • SpliceAI max delta 0.30 (possible splice impact).
Sources
revelspliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants without predicted splice effect. NM_003002.4:c.110A>T is a missense variant (p.Asp37Val), not a synonymous substitution. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not synonymous.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.30). REVEL score = 0.701. BayesDel score = 0.256688.

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Canadian guideline on genetic screening for hereditary renal cell cancers.
    Reaume MN et al. · 2013
    Canadian guideline proposing referral criteria for genetic assessment of hereditary renal cell cancer. Discusses general genetic screening indications without reference to specific SDHD variants.
    Does not name this variant
    PMID 24319509 ↗
  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. Provides general clinical guidance without discussion of specific SDHD variants or NM_003002.4:c.110A>T.
    Does not name this variant
    PMID 25394175 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ Cancer Genetics Risk Assessment and Counseling summary. Overview of cancer genetics risk assessment with no mention of specific SDHD variants.
    Does not name this variant
    PMID 26389258 ↗
  • ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG).
    Miller DT et al. · 2022
    ACMG SF v3.1 policy statement listing genes recommended for secondary findings reporting. SDHD is included as a secondary finding gene, but no specific variants are discussed.
    Does not name this variant
    PMID 35802134 ↗
  • Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
    Lenders JW et al. · 2014
    Endocrine Society clinical practice guideline for pheochromocytoma and paraganglioma. Provides management recommendations and mentions SDHD as a susceptibility gene but does not discuss specific variants.
    Does not name this variant
    PMID 24893135 ↗

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.300 Open source ↗
ClinVar 1 Uncertain significance · 1 Likely pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 940748)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.30). REVEL score = 0.701. BayesDel score = 0.256688.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SDHD, a subunit of succinate dehydrogenase, is infrequently altered in cancer.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.