Variant classification summary

NM_004168.4:c.1657G>A

SDHA · NP_004159.2:p.(Asp553Asn) · NM_004168.4

GRCh37: chr5:251212 G>A · GRCh38: chr5:251097 G>A

Gene: SDHA Transcript: NM_004168.4

Final call

VUS

PM2 supporting

Variant details

Gene

SDHA

Transcript

NM_004168.4

Protein

NP_004159.2:p.(Asp553Asn)

gnomAD AF

1.7993780356748413e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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).

4

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	pvs1_variant_assessment
PS1	N/A	No 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.	pm5_candidates
PS2	N/A	No de novo observation has been reported for this variant. No maternity/paternity-confirmed de novo data available.
PS3	Not assessed	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.	oncokb
PS4	Not assessed	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.	clinvar
PS5	N/A	Insufficient evidence to apply PS5; this criterion is typically reserved for variants identified through newborn screening or other validated screening programs, not applicable here.
PM1	Not met	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.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	N/A	No de novo observation has been reported for this variant. No maternity/paternity-confirmed de novo data available to support PM6.
PP1	N/A	No co-segregation data with disease in affected family members is available for this variant.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	N/A	No patient-specific phenotype or detailed clinical data are available for assessment of phenotypic specificity or highly specific phenotype matching for SDHA-associated disease.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	N/A	No observation of this variant in trans with a known pathogenic variant in SDHA, and no homozygous observations in gnomAD. Insufficient data to apply BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	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.	oncokb
BS4	N/A	No family segregation data are available for this variant. BS4 requires observation of lack of co-segregation with disease in affected family members.
BP1	Not met	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.	pvs1_gene_context
BP2	N/A	No 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.
BP4	Not met	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.	revel bayesdel spliceai
BP5	N/A	No cases have been reported where this variant is found in an individual with an alternate molecular basis for disease. Insufficient data to apply BP5.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.