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.1 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.2 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).3 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).4
SDHA
Final classification
VUS
SDHA c.1657G>A · p.Asp553Asn
SDHA
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.
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.
Classification rationale
PM2
VUS
SDHA c.1657G>A
PM2
→
VUS
2
revelbayesdelspliceai ↗
4
PMID:25741868 ↗generic_acmg_combination_rules
Gene diagram
· NM_004168.4 · variants mapped to exon structure
SDHA
NM_004168.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 12 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
gnomAD v2.1: AF=3.58e-05 (9/251134)0 homozygotes
Assessed · not applied
Pathogenic
PS3
No variant-specific functional studies (enzymatic activity, protein interaction, cellular assays) have been identified for NM_004168.4:c.1657G>A (p.Asp553Asn).
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.
PM1
Residue Asp553 is not located in a statistically significant mutational hotspot.
PP2
SDHA is a gene where missense variants are a known disease mechanism (PPGL, GIST, RCC).
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.
PP5
ClinVar reports this variant as Uncertain significance across 4 clinical laboratories with review status 'criteria provided, single submitter'.
Benign
BA1
The highest subpopulation allele frequency is 0.023% (NFE_SWE in gnomAD v2.1), far below the 1% BA1 threshold.
BS1
The highest subpopulation allele frequency is 0.023% (NFE_SWE in gnomAD v2.1), far below the 0.3% BS1 threshold.
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.
BP1
Missense variants in SDHA are a known disease mechanism.
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.
BP6
ClinVar classification for this variant is Uncertain significance (4 clinical laboratories).
N/A · 12
PVS1 · PS1 · PS2 · PM5 · PM6 · PP1 · PP4 · BS2 · BS4 · BP2 · BP5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0018%
· 29 / 1,611,668
0 hom · FAF 0.0015%
0 hom · FAF 0.0015%
Remaining individuals 2 / 62,282 |
0.0032% |
European (non-Finnish) 25 / 1,179,672 |
0.0021% |
European (Finnish) 1 / 64,034 |
0.0016% |
African/African American 1 / 74,844 |
0.0013% |
+ 6 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0036%
· 9 / 251,134
0 hom · FAF 0.0041%
0 hom · FAF 0.0041%
European (non-Finnish) 9 / 113,422 |
0.0079% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 5 PMIDs not cited in assessment
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.
CLINVAR
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.
CLINVAR
28878254 ↗
Germline Mutations in Cancer Predisposition Genes are Frequent in Sporadic Sarcomas.
CLINVAR
24893135 ↗
Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
CLINVAR