About SDHA
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SDHA c.1657G>A, p.(Asp553Asn)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present in gnomAD at extremely low allele frequency (v2.1: AF=0.0036%, 9/251,134 alleles; v4.1: AF=0.0018%, 29/1,611,668 alleles), with no homozygotes observed. The highest subpopulation frequency is 0.023% in NFE_SWE (v2.1), well below the 0.1% PM2 threshold for non-VCEP assessment. Absent from gnomAD-Canada.
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; combination = 1 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
29 / 1,611,668 alleles
gnomAD v4.1: 29 / 1,611,668 alleles. Recorded AF 1.79938e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.58374e-05; MAF= 0.00358%, 9/251134 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.93497e-05; MAF= 0.00793%, 9/113422 alleles, homozygotes = 0); grpmax FAF= 4.125e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
4 reported laboratory submissions
4 Uncertain significance. 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. SDHA, a subunit of succinate dehydrogenase, is frequently altered by amplification in various cancers, including lung and bladder cancers.
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 8 not met · 4 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_004168.4:c.1657G>A (p.Asp553Asn) is a missense variant in SDHA, present in gnomAD at extremely low allele frequency (v2.1: 0.0036%, 9/251,134 alleles; v4.1: 0.0018%, 29/1,611,668 alleles; 0 homozygotes), satisfying PM2 at supporting strength.
In silico predictions are conflicting: REVEL (0.774) predicts damaging, while BayesDel (-0.066) predicts benign. SpliceAI (delta 0.00) predicts no splicing impact. PP3 is not met due to lack of convergent computational evidence.
No variant-specific functional studies, case-control data, segregation data, or de novo observations have been identified in the literature. ClinVar reports this variant as Uncertain significance (4 clinical laboratories, criteria provided, single submitter).
Under generic ACMG/AMP 2015 classification rules (PMID:25741868), a single supporting pathogenic criterion (PM2_supporting) with no benign criteria met results in a classification of Variant of Uncertain Significance (VUS).
No criteria match.
Met · 1
PM2 SupportingThis variant is present in gnomAD at extremely low allele frequency (v2.1: AF=0.0036%, 9/251,134 alleles; v4.1: AF=0.0018%, 29/1,611,668 alleles), with no homozygotes observed. The highest subpopulation frequency is 0.023% in NFE_SWE (v2.1), well below the 0.1% PM2 threshold for non-VCEP assessment. Absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=3.58e-05 (9/251
- 134)
- 0 homozygotes
- grpmax FAF=4.13e-05
- gnomAD v4.1: AF=1.80e-05 (29/1
- 611
- 668)
- grpmax FAF=1.46e-05
- Highest subpopulation AF: 0.023% (NFE_SWE
- v2.1) — all subpopulations <0.1%
- gnomAD-Canada v1.0: absent
Sources
Not met · 8 · evaluated, threshold not reached
PM1 Residue Asp553 is not located in a statistically significant mutational hotspot. Hotspot analysis confirms this variant does not lie in a recognized functional domain or enrichment region for pathogenic variation in SDHA. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue_significant=false
- exact_variant_listed='no'. No statistically significant clustering at codon 553.
PP3 In silico predictions are conflicting: REVEL score of 0.774 supports a deleterious effect, but BayesDel score of -0.066 predicts a benign effect. SpliceAI delta score of 0.00 indicates no splicing impact. Multiple lines of computational evidence do not converge on a deleterious prediction, failing the PP3 requirement for convergent in silico support. Details ▾Hide ▴
Evidence considered
- REVEL: 0.774 (damaging
- above 0.5 threshold)
- BayesDel: -0.066 (benign
- below 0.0 threshold — conflicting)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
PP5 ClinVar reports this variant as Uncertain significance across 4 clinical laboratories with review status 'criteria provided, single submitter'. No expert panel or reputable source (clinical practice guideline, professional society) classifies this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: 4 clinical laboratories
- all VUS. No expert panel or authoritative source reports pathogenic classification.
Sources
BA1 The highest subpopulation allele frequency is 0.023% (NFE_SWE in gnomAD v2.1), far below the 1% BA1 threshold. This variant is not common enough in any population to meet BA1. Details ▾Hide ▴
Evidence considered
- Max subpopulation AF (v2.1): NFE_SWE = 0.023% (6/26
- 134)
- Max subpopulation AF (v4.1): Remaining = 0.0032% (2/62
- 282)
- All subpopulation AFs << 1% BA1 threshold
Sources
BS1 The highest subpopulation allele frequency is 0.023% (NFE_SWE in gnomAD v2.1), far below the 0.3% BS1 threshold. This variant is not sufficiently common in any population to meet BS1. Details ▾Hide ▴
Evidence considered
- Max subpopulation AF (v2.1): NFE_SWE = 0.023% (6/26
- 134)
- Max subpopulation AF (v4.1): Remaining = 0.0032% (2/62
- 282)
- All subpopulation AFs << 0.3% BS1 threshold
Sources
BP1 Missense variants in SDHA are a known disease mechanism. Pathogenic missense variants in SDHA have been reported in association with hereditary paraganglioma-pheochromocytoma syndromes, GIST, and renal cell carcinoma. BP1 is applicable only when primarily truncating variants cause disease, which is not the case for SDHA. Details ▾Hide ▴
Evidence considered
- SDHA loss-of-function mechanism is supported
- but missense variants are also an established disease mechanism (PPGL
- GIST
- RCC). Both missense and truncating variants are pathogenic.
Sources
pvs1_gene_context
BP4 REVEL score of 0.774 supports a deleterious effect on protein function, directly contradicting the BP4 requirement for multiple lines of computational evidence suggesting no impact on gene product. BP4 cannot be applied when a predictor in the damaging range is present. Details ▾Hide ▴
Evidence considered
- REVEL: 0.774 (damaging — contradicts benign prediction)
- BayesDel: -0.066 (benign)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
BP6 ClinVar classification for this variant is Uncertain significance (4 clinical laboratories). No reputable source classifies this variant as benign or likely benign. BP6 requires a reputable source to report the variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: 4 clinical labs
- all VUS. No source reports benign or likely benign classification.
Sources
Not assessed · 4 · no assessment recorded
PS3 No variant-specific functional studies (enzymatic activity, protein interaction, cellular assays) have been identified for NM_004168.4:c.1657G>A (p.Asp553Asn). OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-level functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional data curated.
Still missing
- No functional assay data available for p.Asp553Asn. In vitro or in vivo studies assessing SDHA enzymatic activity or complex assembly would be informative.
Sources
PS4 The variant has been observed in ClinVar (4 clinical laboratories, all reporting VUS), but no case-control or cohort study comparing variant frequency in affected vs. unaffected individuals has been identified. Literature review did not yield variant-specific case counts meeting PS4 thresholds. Details ▾Hide ▴
Evidence considered
- ClinVar: 4 clinical laboratory submissions
- all VUS. No case-control comparison data available.
Still missing
- No case-control or case-count studies of this variant in SDHA-associated disease cohorts (PPGL
- GIST
- RCC) are available.
Sources
PP2 SDHA is a gene where missense variants are a known disease mechanism (PPGL, GIST, RCC). However, gnomAD constraint metrics (missense Z-score, o/e ratio) required to determine whether SDHA has a low rate of benign missense variation are not available in the provided data. PP2 cannot be applied without this information. Details ▾Hide ▴
Evidence considered
- SDHA missense variants are associated with disease
- but constraint metrics are unavailable for formal PP2 assessment.
Still missing
- gnomAD gene constraint metrics (missense Z-score
- o/e ratio) not available. Required to determine PP2 eligibility.
BS3 No variant-specific functional studies evaluating the effect of p.Asp553Asn on SDHA protein function (enzymatic activity, complex assembly, succinate accumulation) have been identified in the literature. OncoKB does not curate benign functional evidence for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence of benign impact available.
Still missing
- No functional data testing whether p.Asp553Asn affects SDHA enzymatic activity
- complex II assembly
- or succinate accumulation.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_004168.4:c.1657G>A is a missense substitution (p.Asp553Asn) and does not fall into any PVS1 null-variant category (nonsense, frameshift, or canonical ±1,2 splice consensus). The PVS1 variant assessment confirms variant_bucket='other' with apply_generic_pvs1_framework=false. Details ▾Hide ▴
Evidence considered
- Missense variant
- PVS1 is reserved for null variants per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_variant_assessment
PS1 N/ANo established pathogenic missense variant at residue Asp553 with the same amino acid change (Asp553Asn) has been identified in ClinVar or the literature to satisfy PS1. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found zero same-residue candidates
- no pathogenic comparator with identical amino acid change exists.
Sources
pm5_candidates
PS2 N/ANo de novo observation has been reported for this variant. No maternity/paternity-confirmed de novo data available. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo established pathogenic missense variant at the same residue (Asp553) with a different amino acid change has been identified. PM5 candidates search returned zero same-residue candidates in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidates: total_candidates_seen=0
- same_residue_candidates=0. No pathogenic comparator at Asp553.
Sources
pm5_candidates
PM6 N/ANo de novo observation has been reported for this variant. No maternity/paternity-confirmed de novo data available to support PM6. Details ▾Hide ▴
No further detail was recorded.
PP1 N/ANo co-segregation data with disease in affected family members is available for this variant. Details ▾Hide ▴
No further detail was recorded.
PP4 N/ANo patient-specific phenotype or detailed clinical data are available for assessment of phenotypic specificity or highly specific phenotype matching for SDHA-associated disease. Details ▾Hide ▴
No further detail was recorded.
BS2 N/ANo observation of this variant in trans with a known pathogenic variant in SDHA, and no homozygous observations in gnomAD. Insufficient data to apply BS2. Details ▾Hide ▴
Evidence considered
- 0 homozygotes observed in gnomAD v2.1 and v4.1. No trans configuration data available.
Sources
BS4 N/ANo family segregation data are available for this variant. BS4 requires observation of lack of co-segregation with disease in affected family members. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ANo data on observation of this variant in trans with a known pathogenic variant in a fully penetrant dominant disorder, nor observed in cis. Insufficient data to apply BP2. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ANo cases have been reported where this variant is found in an individual with an alternate molecular basis for disease. Insufficient data to apply BP5. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_004168.4:c.1657G>A is a missense substitution (p.Asp553Asn) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous. BP7 is reserved for silent variants.
PS5 N/AInsufficient evidence to apply PS5; this criterion is typically reserved for variants identified through newborn screening or other validated screening programs, not applicable here. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- SDHA
- Transcript
- NM_004168.4
- Coding (HGVS c.)
- NM_004168.4:c.1657G>A
- Protein (HGVS p.)
- NP_004159.2:p.(Asp553Asn)
- GRCh38
- chr5:251097 G>A
- GRCh37
- chr5:251212 G>A
- ClinVar
- 239654
Gene diagram
Every interpreted variant in SDHA, mapped onto the exon structure of NM_004168.4. Select a row to find it on the plot.
SDHANM_004168.4
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 SDHA
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
29 / 1,611,668 alleles
AF 1.8e-05 · 0 homozygotes · FAF 1.45e-05
gnomAD v2.1
9 / 251,134 alleles
AF 3.58e-05 · 0 homozygotes · FAF 4.12e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.8e-05 · 29 / 1,611,668 alleles · 0 hom · FAF 1.5e-05
| Remaining individuals2 / 62,282 | 3.2e-05 |
| European (non-Finnish)25 / 1,179,672 | 2.1e-05 |
| European (Finnish)1 / 64,034 | 1.6e-05 |
| African/African American1 / 74,844 | 1.3e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 3.6e-05 · 9 / 251,134 alleles · 0 hom · FAF 4.1e-05
| European (non-Finnish)9 / 113,422 | 7.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.79938e-05; MAF= 0.00180%, 29/1611668 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.2112e-05; MAF= 0.00321%, 2/62282 alleles, homozygotes = 0); grpmax FAF= 1.455e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.58374e-05; MAF= 0.00358%, 9/251134 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.93497e-05; MAF= 0.00793%, 9/113422 alleles, homozygotes = 0); grpmax FAF= 4.125e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.774
- BayesDel
- -0.066
How the predictions were used
PP3 In silico predictions are conflicting: REVEL score of 0.774 supports a deleterious effect, but BayesDel score of -0.066 predicts a benign effect. SpliceAI delta score of 0.00 indicates no splicing impact. Multiple lines of computational evidence do not converge on a deleterious prediction, failing the PP3 requirement for convergent in silico support. Details ▾Hide ▴
Evidence considered
- REVEL: 0.774 (damaging
- above 0.5 threshold)
- BayesDel: -0.066 (benign
- below 0.0 threshold — conflicting)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
BP4 REVEL score of 0.774 supports a deleterious effect on protein function, directly contradicting the BP4 requirement for multiple lines of computational evidence suggesting no impact on gene product. BP4 cannot be applied when a predictor in the damaging range is present. Details ▾Hide ▴
Evidence considered
- REVEL: 0.774 (damaging — contradicts benign prediction)
- BayesDel: -0.066 (benign)
- SpliceAI: max delta 0.00 (no splice impact)
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_004168.4:c.1657G>A is a missense substitution (p.Asp553Asn) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous. BP7 is reserved for silent variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.774. BayesDel score = -0.066438.
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
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015ACMG/AMP 2015 standards and guidelines for the interpretation of sequence variants. Provides the generic classification framework and criteria definitions. Does not discuss SDHA or any specific variant.Does not name this variant
-
PMID 20301715 ↗Hereditary Paraganglioma-Pheochromocytoma Syndromes.Adam MP et al. · 1993GeneReviews clinical resource on Hereditary Paraganglioma-Pheochromocytoma Syndromes. Provides gene-level overview of SDHA and other SDHx genes in PPGL. NM_004168.4:c.1657G>A (p.Asp553Asn) is not discussed.Does not name this variant
-
PMID 25394175 ↗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.Hampel H et al. · 2015ACMG/NSGC practice guideline for referral indications for cancer predisposition assessment. Lists hereditary cancer syndromes and referral criteria. SDHA is mentioned in the context of hereditary paraganglioma-pheochromocytoma syndromes. NM_004168.4:c.1657G>A is not discussed.Does not name this variant
-
PMID 28878254 ↗Germline Mutations in Cancer Predisposition Genes are Frequent in Sporadic Sarcomas.Chan SH et al. · 2017Reports germline mutations in cancer predisposition genes among 162 sporadic sarcoma patients using a targeted 80-gene panel that included SDHA. NM_004168.4:c.1657G>A (p.Asp553Asn) was not identified in this cohort.Does not name this variant
-
PMID 24893135 ↗Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.Lenders JW et al. · 2014Endocrine Society clinical practice guideline for pheochromocytoma and paraganglioma. Provides gene-level discussion of SDHx genes including SDHA. NM_004168.4:c.1657G>A (p.Asp553Asn) is not discussed.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
29 / 1,611,668 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
4 Uncertain significance
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/239654/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/5-251212-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr5-251097-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/5-251097-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004168.4%3Ac.1657…
- OncoKB ↗www.oncokb.org/gene/SDHA/D553N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SDHA+c.1657G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.79938e-05; MAF= 0.00180%, 29/1611668 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.2112e-05; MAF= 0.00321%, 2/62282 alleles, homozygotes = 0); grpmax FAF= 1.455e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.58374e-05; MAF= 0.00358%, 9/251134 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.93497e-05; MAF= 0.00793%, 9/113422 alleles, homozygotes = 0); grpmax FAF= 4.125e-05.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 239654)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.774. BayesDel score = -0.066438.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SDHA, a subunit of succinate dehydrogenase, is frequently altered by amplification in various cancers, including lung and bladder cancers.
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.