Variant classification summary

NM_003002.4:c.281C>G

SDHD · NP_002993.1:p.(Ser94Cys) · NM_003002.4

GRCh37: chr11:111959702 C>G · GRCh38: chr11:112088978 C>G

Gene: SDHD Transcript: NM_003002.4

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

SDHD

Transcript

NM_003002.4

Protein

NP_002993.1:p.(Ser94Cys)

gnomAD AF

3.7173984158926216e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 supporting reflects an extremely low gnomAD v4.1 frequency with zero homozygotes.

2

VUS: PP3 moderate reflects a REVEL score of 0.8 above the calibrated moderate threshold of 0.773.

Final determination: Under the generic ACMG/AMP 2015 fallback, one moderate criterion plus one supporting criterion satisfies no pathogenic, likely pathogenic, benign, or likely benign rule, resulting in VUS.

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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic variant with the same p.Ser94Cys amino-acid change was identified; the exact variant remains ClinVar uncertain significance.	clinvar PMID:17576205
PS2	Not assessed	Not assessed: confirmed maternity, paternity, de novo status, and absence of family history are not documented for c.281C>G.	PMID:25741868 PMID:17576205
PS3	Not assessed	Not assessed: no variant-specific functional assay or validated damaging-effect result was reported for SDHD c.281C>G (p.Ser94Cys).
PS4	Not assessed	Not assessed: no exact-variant affected-versus-control counts or odds ratio with a 95% confidence interval are available to evaluate PS4.	PMID:19454582 PMID:20664475 PMID:24319509 PMID:17576205
PM1	Not assessed	Not assessed: no authoritative SDHD critical-domain map or benign-variation analysis establishes whether residue 94 qualifies for PM1.	hotspots
PM2	Met	Met at supporting: gnomAD v4.1 AF is 3.7174e-06 with zero homozygotes, below the <=0.0001 PM2 threshold.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	N/A	Not applicable: available SDHD disease-context evidence describes hereditary paraganglioma/pheochromocytoma as autosomal dominant, not recessive.	PMID:20664475 PMID:24319509
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no qualifying pathogenic different missense change at SDHD residue 94 was identified for comparison with p.Ser94Cys.	PMID:17576205
PM6	Not assessed	Not assessed: no variant-specific assumed de novo observation or parental genotype information is documented.	PMID:25741868 PMID:17576205
PP1	Not assessed	Not assessed: no affected-relative segregation or informative meioses are reported for c.281C>G.	PMID:25741868 PMID:17576205
PP2	Not assessed	Not assessed: SDHD-specific evidence for both low benign-missense variation and a common missense disease mechanism is unavailable.
PP3	Met	Met at moderate strength: REVEL 0.8 exceeds the missense PP3 threshold of >=0.773.	revel
PP4	Not assessed	Not assessed: the case lacks a documented patient phenotype or family history shown to be highly specific for a single-gene disease.	PMID:20664475 PMID:24319509
PP5	Not assessed	Not assessed: exact-variant ClinVar is Uncertain significance with zero expert-panel submissions, and no reputable pathogenic report was verified.	clinvar PMID:19454582 PMID:17576205
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 5.53e-06 versus the >=0.05 BA1 threshold.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 5.53e-06, far below the supplied 0.01 generic BS1 default.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes but does not document a confirmed healthy adult SDHD heterozygote with expected full early-age penetrance.	gnomad_v4 gnomad_v2 PMID:24319509 PMID:20664475
BS3	Not assessed	Not assessed: no variant-specific functional assay demonstrated preserved SDHD protein function or normal splicing for c.281C>G (p.Ser94Cys).
BS4	Not assessed	Not assessed: no affected relatives lacking c.281C>G are documented, so non-segregation cannot be evaluated.	PMID:25741868 PMID:17576205
BP1	Not assessed	Not assessed: the available evidence does not show that SDHD disease is caused primarily by truncating rather than missense variants.
BP2	Not assessed	Not assessed: no parent-tested phase or co-occurrence observation shows c.281C>G in trans or cis with a pathogenic variant.	PMID:20664475 PMID:24319509
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.8 is above the missense BP4 supporting threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no case links this exact variant to disease caused by an independently established alternate molecular basis.
BP6	Not assessed	Not assessed: exact-variant ClinVar is Uncertain significance with zero expert-panel submissions, and no reputable benign report was verified.	clinvar PMID:19454582 PMID:17576205
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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