Variant classification summary

NM_003000.3:c.137G>A

SDHB · NP_002991.2:p.(Arg46Gln) · NM_003000.3

GRCh37: chr1:17371319 C>T · GRCh38: chr1:17044824 C>T

Gene: SDHB Transcript: NM_003000.3

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP1 supporting PP3 supporting

Variant details

Gene

SDHB

Transcript

NM_003000.3

Protein

NP_002991.2:p.(Arg46Gln)

gnomAD AF

1.673017938470118e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 strong is supported by markedly accelerated R46Q protein degradation.

2

Likely Pathogenic: PM2 supporting is supported by an extremely low gnomAD filtering frequency and zero homozygotes.

3

Likely Pathogenic: PP1 supporting is supported by disease-associated segregation in family F04.

4

Likely Pathogenic: PP3 supporting is supported by REVEL 0.911 exceeding the calibrated threshold.

Final determination: Under generic ACMG/AMP 2015 fallback rules, one strong pathogenic criterion plus at least two supporting pathogenic criteria supports Likely Pathogenic; here PS3 strong combines with PM2, PP1, and PP3 supporting.

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: all cited Arg46Gln reports use the same c.137G>A nucleotide change, with no alternate nucleotide change producing Arg46Gln demonstrated.	PMID:12618761 PMID:18362451 PMID:23083876
PS2	Not met	Not met: the variant was reported with paternal inheritance in family F04, not as a de novo variant with confirmed maternity and paternity.	PMID:12618761 PMID:18362451
PS3	Met	Met, strong: R46Q SDHB half-life was 1.73 hours versus 11.23 hours for wild type in a pulse-chase assay.	PMID:22835832
PS4	Not met	Not met: 1/7 affected probands versus 0/100 normal alleles gives OR infinity, but the exact 95% CI is approximately 0.366 to infinity and includes 1.	PMID:12618761 PMID:18362451 PMID:23083876
PM1	Not met	Not met: Cancer Hotspots found no statistically significant SDHB R46 hotspot, and the VCEP domain_tables entry for SDHB is absent.	cspec hotspots
PM2	Met	Met at supporting strength: gnomAD v4.1 grpmax FAF is 1.298e-05, below the PM2 threshold of 0.0001, with zero observed homozygotes.	gnomad_v4 gnomad_v2 cspec
PM3	N/A	Not applicable: SDHB hereditary pheochromocytoma-paraganglioma is specified as autosomal dominant, whereas PM3 requires a recessive disorder.	cspec PMID:12618761 PMID:18362451
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: the comparator artifact found zero candidates, and no verified pathogenic alternate missense change at SDHB Arg46 is supplied.	pm5_candidates
PM6	Not met	Not met: reported paternal inheritance and transmission to an affected proband's son contradict an assumed de novo occurrence.	PMID:12618761 PMID:18362451
PP1	Met	Met at supporting: family F04 had the variant, a paraganglioma-affected proband, and additional affected relatives, although individual relative genotypes require pedigree confirmation.	PMID:12618761 PMID:18362451
PP2	Not assessed	Not assessed: no gene-level benign-missense rate or documented threshold showing missense variants are a common SDHB disease mechanism is supplied.	PMID:12618761 PMID:23083876
PP3	Met	Met at supporting strength: REVEL 0.911 exceeds the generic PP3 supporting threshold of 0.644 for missense variants.	revel
PP4	Not assessed	Not assessed: the current patient's phenotype and family history are not available, and the reported disease has multiple genetic etiologies.	PMID:12618761 PMID:18362451
PP5	Not met	Not met: ClinVar reports Pathogenic/Likely pathogenic submissions, but there is no exact-variant ClinVar expert-panel classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.298e-05, far below the generic BA1 stand-alone threshold of 0.05.	gnomad_v4 gnomad_v2 cspec
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 1.298e-05, far below the generic BS1 default threshold of 0.01.	gnomad_v4 gnomad_v2 cspec
BS2	Not assessed	Not assessed: an asymptomatic R46Q carrier was reported, but healthy-adult status, age, and full early-age penetrance were not established.	PMID:18362451 cspec
BS3	Not met	Not met: R46Q degraded faster than wild type, with a 1.73-hour versus 11.23-hour protein half-life in pulse-chase testing.	PMID:22835832
BS4	Not met	Not met: no affected non-carrier is reported; the Japanese family instead includes an unaffected R46Q carrier.	PMID:12618761 PMID:18362451
BP1	Not met	Not met: an SDHB RCC cohort reported four missense variants versus one nonsense variant, and p.Arg46Gln was observed in affected families.	PMID:12618761 PMID:23083876 PMID:22835832
BP2	Not assessed	Not assessed: family reports identify only heterozygous p.Arg46Gln and no pathogenic variant documented in cis or trans.	cspec PMID:12618761 PMID:18362451
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 0.911 is above the generic BP4 supporting cutoff of 0.29 for missense variants.	revel
BP5	Not assessed	Not assessed: no alternate molecular basis for disease is documented for the current case or the reported R46Q cases.	PMID:12618761 PMID:18362451
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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