Variant classification summary

NM_003000.3:c.744C>G

SDHB · NP_002991.2:p.(Asn248Lys) · NM_003000.3

GRCh37: chr1:17349124 G>C · GRCh38: chr1:17022629 G>C

Gene: SDHB Transcript: NM_003000.3

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

SDHB

Transcript

NM_003000.3

Protein

NP_002991.2:p.(Asn248Lys)

gnomAD AF

6.196040234606868e-07 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): the variant is nearly absent from population databases, with a gnomAD v4.1 allele frequency of 6.2e-07 (1/1,613,934 alleles).

2

PP3 (Supporting): the missense REVEL score of 0.866 exceeds the calibrated threshold of >0.750.

3

Classification: VUS - only PM2 and PP3 are met, below the ACMG/AMP 2015 combination thresholds for a pathogenic or benign call.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds; therefore, the variant is classified as a 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	Not applicable: this missense substitution yields p.Asn248Lys, so no nonsense-mediated decay, truncation, or canonical splice disruption mechanism applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: the reported p.N248K publication describes the same c.744C>G change, not a distinct nucleotide substitution producing the same amino acid.	PMID:18551016
PS2	Not assessed	Not assessed: no parental genotypes or maternity/paternity confirmation were available to establish de novo occurrence.
PS3	Not assessed	Not assessed: no functional assay tested p.Asn248Lys; the available publications provide only clinical screening or non-variant-specific context.	cspec PMID:18551016 PMID:15989954 PMID:25720320
PS4	Not assessed	Not assessed: only one affected individual is reported, with no case-control comparison, cohort denominator, or statistical enrichment available.	PMID:18551016
PM1	Not assessed	Not assessed: the variant lies at residue 248, immediately outside the reported SDHB iron-sulfur domain boundary (B115-B247), with no approved hotspot designation.	cspec PMID:15989954
PM2	Met	Met (Supporting): the variant is nearly absent from population databases, with a gnomAD v4.1 allele frequency of 6.2e-07 (1/1,613,934 alleles).	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: the single reported case provides no second pathogenic SDHB variant, phase information, or recessive disease context.	cspec PMID:18551016
PM4	N/A	Not applicable: this missense substitution does not change protein length, so there is no in-frame indel or stop-loss event to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic amino-acid substitution at residue 248 was identified, as the report concerns p.N248K itself.	PMID:18551016
PM6	Not assessed	Not assessed: no evidence states the variant was presumed de novo or provides a clinical basis for that presumption.
PP1	Not assessed	Not assessed: only one affected individual is documented, with no affected relatives, informative meioses, or cosegregation analysis.
PP2	Not assessed	Not assessed: SDHB loss of function is the established mechanism, and missense variation is not shown to be a common pathogenic mechanism for this gene.	cspec
PP3	Met	Met (Supporting): the missense REVEL score is 0.866, above the calibrated PP3 threshold of >0.750.	cspec revel
PP4	Not assessed	Not assessed: the reported vagal head-and-neck paraganglioma does not establish phenotype specificity for SDHB-related disease, and no case phenotype data were provided.	PMID:18551016 cspec
PP5	Not met	Not met: the exact ClinVar record has three Likely pathogenic laboratory submissions but no expert-panel submission required for this criterion.	clinvar
BA1	Not met	Not met: the highest ancestry-specific gnomAD v4.1 allele frequency is 8.5e-07, far below the >1% BA1 threshold.	gnomad_v4
BS1	Not met	Not met: the gnomAD v4.1 allele frequency is 6.2e-07, far below the >0.3% BS1 threshold in every population.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not assessed	Not assessed: gnomAD reports one heterozygous allele and no homozygotes, with no evidence establishing unaffected adult carriers or penetrance.	gnomad_v4 cspec
BS3	Not assessed	Not assessed: no functional assay demonstrating preserved SDHB function for p.Asn248Lys was identified.	cspec PMID:18551016 PMID:15989954 PMID:25720320
BS4	Not assessed	Not assessed: no unaffected relatives carrying the variant were reported, and no segregation or clinical data were provided.
BP1	Not assessed	Not assessed: no SDHB-specific evidence shows missense variation is a benign mechanism or that pathogenic missense variation is rare in this gene.	cspec
BP2	Not assessed	Not assessed: no evidence shows this variant in trans with a pathogenic variant, and phase data are insufficient to establish a benign configuration.	cspec PMID:18551016
BP3	N/A	Not applicable: this missense substitution does not alter protein length within a repeat region, so there is no in-frame indel to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: the missense REVEL score of 0.866 is well above the calibrated BP4 threshold of <0.250.	cspec revel
BP5	Not assessed	Not assessed: no alternative molecular diagnosis explaining the phenotype was identified in a carrier of this variant.
BP6	Not met	Not met: no expert-panel Benign or Likely benign classification for this exact variant is present in ClinVar.	clinvar
BP7	N/A	Not applicable: this missense substitution alters the encoded protein, so the silent-variant premise of BP7 does not hold.	generic_acmg_combination_rules

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