Variant classification summary

NM_004168.4:c.163T>C

SDHA · NP_004159.2:p.(Tyr55His) · NM_004168.4

GRCh37: chr5:224487 T>C · GRCh38: chr5:224372 T>C

Gene: SDHA Transcript: NM_004168.4

Final call

Benign

BA1 stand-alone benign BS1 strong benign BS2 supporting benign BP4 supporting benign BP6 supporting benign

Variant details

Gene

SDHA

Transcript

NM_004168.4

Protein

NP_004159.2:p.(Tyr55His)

gnomAD AF

0.0007692088367901243 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_004168.4:c.163T>C (p.Tyr55His) is classified as Benign based on the ACMG/AMP 2015 framework.

2

This variant meets BA1 (stand-alone benign): the allele frequency in the East Asian population is 1.96% in gnomAD v2.1 (391/19,954 alleles, 5 homozygotes) and 2.39% in gnomAD v4.1 (1,074/44,890 alleles, 10 homozygotes), with a gnomAD v4.1 grpmax FAF of 2.27%. An allele frequency exceeding 1% in a general population is inconsistent with a role in rare Mendelian disease.

3

Additional benign evidence includes BS1 (East Asian AF well above 0.3%), BS2 (12 homozygotes observed in gnomAD v4.1 in a gene where biallelic loss-of-function causes severe early-onset recessive disease), BP4 (REVEL = 0.392; BayesDel = 0.00237; SpliceAI max delta = 0.03; all predictors converge on a benign interpretation), and BP6 (ClinVar consensus of Benign/Likely benign from 11 clinical laboratories).

4

No pathogenic criteria are met. PVS1 is not applicable (missense variant). PP3 is not met (in silico predictors favor benign). PM1 is not met (the variant is common in population databases despite lying in the FAD-binding domain). PS4 is not met (the variant is classified as benign across clinical laboratories and observed at appreciable frequency in unaffected populations).

5

The classification of Benign is driven by BA1, which alone is sufficient to classify a variant as Benign under the ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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.163T>C is a missense variant (p.Tyr55His), not a predicted null variant. It does not fall into the default generic PVS1 buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. SpliceAI predicts no significant splice impact (max delta score = 0.03). The generic PVS1 framework is not applicable.	pvs1_generic_framework spliceai
PS1	Not assessed	No alternate nucleotide change at the same amino acid position with an established pathogenic classification was identified. PS1 cannot be applied without a known pathogenic comparator with the same amino acid change from a different nucleotide substitution.
PS2	Not assessed	No de novo occurrence of this variant in a patient with disease and confirmed paternity/maternity was identified in the literature or databases. No case report or database entry explicitly states a de novo observation of p.Tyr55His.
PS3	Not assessed	No published functional studies specifically evaluating the functional impact of NM_004168.4:c.163T>C (p.Tyr55His) were identified. The Kent et al. 2024 paper (PMID:39321216) describes an SDHA functional assay platform but does not specifically mention this variant in the available abstract, and no full-text is available for confirmation. Well-established functional evidence showing a damaging effect is absent.
PS4	Not met	No case-control study demonstrating a statistically significant enrichment of this variant in affected individuals compared to controls was identified. ClinVar submissions report the variant as Benign/Likely benign across multiple clinical laboratories, which is inconsistent with PS4. The observed population frequency in gnomAD (v4.1 total AF = 0.077%, v2.1 total AF = 0.148%) further argues against disease association.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	PS5 applies when a different nucleotide change at the same position has been reported as pathogenic. No such established pathogenic variant at the same nucleotide position was identified.
PM1	Not met	Residue Tyr55 lies within the FAD-binding domain of SDHA (Rossmann-fold motif). However, no ClinGen- or VCEP-defined mutational hotspot or critical domain specification exists for SDHA PM1 adjudication. Furthermore, gnomAD population data show the variant is common in East Asian populations (AF ~2%), and multiple homozygotes are observed (n=10-12), which is inconsistent with a critical functional domain where missense variation is absent or rare. PM1 is not met.	gnomad_v2 gnomad_v4
PM2	Not met	In gnomAD v4.1, the total allele frequency is 0.00077 (0.077%), which is below the 0.1% threshold. However, in gnomAD v2.1, the total AF is 0.00148 (0.148%), above 0.1%. More critically, BA1 is met (East Asian AF >1% in both v2.1 and v4.1), which is mutually exclusive with PM2. PM2 is not applied.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	No reports of this variant occurring in trans with a known pathogenic or likely pathogenic variant in a recessive SDHA-associated disorder (e.g., mitochondrial complex II deficiency, Leigh syndrome) were identified.
PM4	N/A	PM4 applies to protein-length-altering variants (in-frame deletions/insertions, stop-loss). NM_004168.4:c.163T>C is a single-nucleotide missense substitution. PM4 is not applicable.
PM5	Not assessed	Automated PM5 candidate harvesting was unable to identify same-residue comparator variants with pathogenic classifications satisfying classic PM5 semantics. No alternate missense at Tyr55 with a known pathogenic classification was found. PM5 cannot be applied.
PM6	Not assessed	No assumed de novo observation (without confirmation of paternity/maternity) was identified for this variant. No clinical testing report or publication lists p.Tyr55His as a de novo finding.
PP1	Not assessed	No family cosegregation data were identified for NM_004168.4:c.163T>C. No multi-case family study mentioning this variant with segregation analysis was found.
PP2	Not assessed	PP2 requires a low rate of benign missense variation and a high rate of pathogenic missense variants in the gene. SDHA has both pathogenic missense and truncating variants reported in association with PPGL, GIST, and Leigh syndrome. However, gene-specific missense constraint metrics (e.g., gnomAD missense Z-score, regional constraint) were not comprehensively assessed, and the observed high population frequency of this specific missense (East Asian AF ~2%) complicates a generic PP2 application. PP2 is not assessed without formal gene-level missense constraint evaluation.
PP3	Not met	Multiple in silico predictors suggest a benign effect for this missense variant. REVEL score is 0.392 (below the 0.5 threshold typically used for damaging prediction). BayesDel score is 0.00237 (very low, indicating benign). SpliceAI predicts no splice impact (max delta = 0.03). The computational evidence does not support a damaging effect; thus PP3 is not met.	revel bayesdel spliceai
PP4	Not assessed	PP4 requires patient-specific phenotypic and family history information that is highly specific for the disease. No proband-specific clinical data were provided in this case. PP4 is not assessable without detailed patient phenotype information.
PP5	Not met	PP5 requires a reputable source to have recently reported the variant as pathogenic. In ClinVar, this variant is classified as Benign by 6 clinical laboratories, Likely benign by 4, and benign by 1. No submitter classifies this variant as pathogenic or likely pathogenic. PP5 is not met.	clinvar
BA1	Met	This variant has an allele frequency exceeding 1% in the East Asian population across multiple population databases: gnomAD v2.1 East Asian AF = 1.96% (391/19,954 alleles, 5 homozygotes), gnomAD v4.1 East Asian AF = 2.39% (1,074/44,890 alleles, 10 homozygotes), and gnomAD-Canada v1.0 East Asian AF = 1.12% (15/1,338 alleles). The gnomAD v4.1 grpmax FAF is 2.27%, well above the 1% BA1 threshold. This allele frequency is too high to support a causative role in rare Mendelian disease, meeting BA1 (stand-alone benign).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Met	The allele frequency in the East Asian population exceeds 0.3% in all queried population databases: gnomAD v2.1 EAS AF = 1.96%, gnomAD v4.1 EAS AF = 2.39%, gnomAD-Canada EAS AF = 1.12%. The overall frequency is also elevated in gnomAD v2.1 (0.148%) although below 0.3% in gnomAD v4.1 (0.077%). BS1 is met based on the East Asian subpopulation frequency, which is well above the 0.3% threshold. Note: BA1 (stand-alone benign) is also met; BS1 provides additional population-frequency support but is not counted independently when BA1 is applied.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Met	This variant has been observed in the homozygous state in multiple individuals across gnomAD databases: 6 homozygotes in v2.1 (exomes), 12 homozygotes in v4.1 (of which 10 are East Asian), and 0 homozygotes in gnomAD-Canada. SDHA biallelic loss-of-function causes severe, early-onset recessive conditions (mitochondrial complex II deficiency, Leigh syndrome) with expected full penetrance. The observation of 12 apparently healthy adult homozygotes in population databases is inconsistent with a highly penetrant recessive pathogenic variant. BS2 is met at the supporting benign level.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating a neutral (non-damaging) effect of NM_004168.4:c.163T>C (p.Tyr55His) were identified. The Kent et al. 2024 paper (PMID:39321216) describes an SDHA functional assay platform but does not specifically mention this variant in the available abstract, and no full-text is available for confirmation. BS3 cannot be assessed without variant-specific functional data.
BS4	Not assessed	No evidence of non-segregation of this variant with disease in affected families was identified. No report of an affected family member lacking the variant within a family segregating SDHA-associated disease was found.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. While SDHA has pathogenic truncating variants, it also has well-established pathogenic missense variants associated with PPGL, GIST, and Leigh syndrome. The gene does not meet the criterion that primarily truncating variants cause disease; therefore BP1 is not met.
BP2	Not assessed	No observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern, was identified. No co-occurrence or phasing data were found in gnomAD or published literature for this specific variant.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_004168.4:c.163T>C is a single-nucleotide missense substitution. BP3 is not applicable.
BP4	Met	Multiple in silico predictors consistently suggest a benign effect for this missense variant. REVEL score is 0.392 (below the commonly used 0.5 pathogenic threshold). BayesDel score is 0.00237 (very low, strongly favoring benign). SpliceAI predicts no significant splice alteration (max delta score = 0.03). The convergent computational evidence supports a lack of functional impact, meeting BP4 at the supporting benign level.	revel bayesdel spliceai
BP5	Not assessed	BP5 applies when an alternate molecular basis for disease has been identified in a case with a different pathogenic variant. No such information is available for this case.
BP6	Met	This variant has been reported in ClinVar as Benign by 6 clinical laboratories, Likely benign by 4 clinical laboratories, and benign by 1 clinical laboratory (ClinVar Variation ID: 353201). The aggregate ClinVar consensus is Benign/Likely benign with 11 submitting laboratories, though none represent an expert panel. BP6 is met at the supporting benign level based on the consistent benign classification across multiple clinical testing laboratories.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence. NM_004168.4:c.163T>C is a missense variant (p.Tyr55His), not a synonymous variant. BP7 is not applicable.

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