Variant classification summary

NM_003000.3:c.434A>G

SDHB · NP_002991.2:p.(Asn145Ser) · NM_003000.3

GRCh37: chr1:17354350 T>C · GRCh38: chr1:17027855 T>C

Gene: SDHB Transcript: NM_003000.3

Final call

VUS

PM2 supporting

Variant details

Gene

SDHB

Transcript

NM_003000.3

Protein

NP_002991.2:p.(Asn145Ser)

gnomAD AF

6.246080584433268e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 supporting is met because the gnomAD v4.1 allele frequency is 6.25e-7 with one allele and zero homozygotes.

2

VUS: PM2 alone does not satisfy a generic ACMG/AMP pathogenic, likely pathogenic, benign, or likely benign combination rule.

Final determination: Because only one supporting pathogenic criterion, PM2, is applied, no generic ACMG/AMP 2015 pathogenic, likely pathogenic, benign, or likely benign combination rule is satisfied; therefore the call is 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 assessed	Not assessed: no established pathogenic variant producing the same p.Asn145Ser amino-acid change was identified in the available evidence.	clinvar spliceai
PS2	Not assessed	Not assessed: parental genotypes, confirmed maternity and paternity, disease status, and family history are not documented.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or reproducible damaging result was identified for SDHB c.434A>G (p.Asn145Ser).
PS4	Not assessed	Not assessed: no variant-specific affected/control counts, odds ratio or relative risk, and 95% confidence interval are available for comparison with >5.0 and 1.0.	PMID:20065170 PMID:20301715 PMID:20664475 PMID:26324357
PM1	Not assessed	Not assessed: residue 145 has no supplied authoritative domain or qualifying hotspot evidence establishing a critical region without benign variation.	cspec hotspots cosmic
PM2	Met	Met at supporting strength: gnomAD v4.1 AF is 6.25e-7, below the <=0.0001 PM2 threshold, with one allele and zero homozygotes.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: SDHB hereditary pheochromocytoma-paraganglioma is autosomal dominant, whereas PM3 is restricted to recessive disorders.	cspec PMID:20664475
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 confirmed pathogenic alternate missense change at SDHB residue Asn145 was identified in the supplied evidence.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no evidence supports an assumed de novo occurrence or provides parental testing for this variant.
PP1	Not assessed	Not assessed: no affected family members, variant genotypes, or informative meioses are documented for co-segregation analysis.
PP2	Not assessed	Not assessed: one rare gnomAD observation (AF 6.24608e-07) does not establish gene-wide benign-missense constraint or a common missense disease mechanism.	gnomad_v4 PMID:20664475
PP3	Not met	Not met: missense REVEL score 0.584 is below the generic PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: the case lacks a documented patient phenotype or family history that is highly specific for a single-gene disease.	PMID:20664475
PP5	Not met	Not met: exact-variant ClinVar records contain two laboratory uncertain-significance submissions and zero expert-panel pathogenic classifications.	clinvar
BA1	Not assessed	Not assessed: gnomAD v4.1 reports AF 6.25e-7, but the required grpmax FAF for the stand-alone 5% BA1 threshold is unavailable.	gnomad_v4
BS1	Not assessed	Not assessed: AF is 6.25e-7, but grpmax FAF and the prevalence, penetrance, and allelic-heterogeneity inputs needed for a BS1 threshold are unavailable.	gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes, but no individual-level healthy-adult observation or phenotype data are available for BS2.	gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated functional assay or reproducible benign functional result was identified for SDHB c.434A>G (p.Asn145Ser).
BS4	Not assessed	Not assessed: no affected, variant-negative relatives or family phenotype data are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: SDHB loss-of-function disease context is present, but no supplied evidence shows that disease is caused primarily by truncating variants.	PMID:20664475
BP2	Not assessed	Not assessed: no parental or offspring testing documents this variant in cis or trans with a pathogenic variant.	clinvar cspec
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: missense REVEL score 0.584 is above the generic BP4 supporting threshold of 0.29.	revel
BP5	Not assessed	Not assessed: no case evidence documents an alternate molecular basis for disease in a carrier of this variant.
BP6	Not met	Not met: exact-variant ClinVar records contain two laboratory uncertain-significance submissions and no expert-panel benign classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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.