Submissions for variant NM_003000.3(SDHB):c.403G>A (p.Val135Met)

gnomAD frequency: 0.00012  dbSNP: rs201585157

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163306	SCV000213834	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	The p.V135M variant (also known as c.403G>A), located in coding exon 4 of the SDHB gene, results from a G to A substitution at nucleotide position 403. The valine at codon 135 is replaced by methionine, an amino acid with highly similar properties. This alteration was identified in 1 of 572 individuals who underwent exome sequencing due to a phenotype unrelated to a history of cancer (atherosclerosis) (Johnston JJ et al. Am. J. Hum. Genet. 2012 Jul;91:97-108). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230410	SCV000287773	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 135 of the SDHB protein (p.Val135Met). This variant is present in population databases (rs201585157, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 41770). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000034687	SCV002038597	uncertain significance	not provided	2024-05-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (PMID: 22703879); This variant is associated with the following publications: (PMID: 22703879)
Sema4, Sema4	RCV000163306	SCV002527072	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-09	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387738	SCV004099562	likely benign	not specified	2023-09-06	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.403G>A (p.Val135Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 364808 control chromosomes (i.e., 22 heterozygotes), predominantly at a frequency of 0.00035 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 40 fold of the estimated maximal expected allele frequency for a pathogenic variant in SDHB causing Pheochromocytoma phenotype (8.8e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.403G>A has been reported in the literature in one individual from a cohort with atherosclerosis phenotypes (e.g., Johnston_2012), however without evidence for causality (e.g., lack of co-segregation or co-occurrence data). This report therefore does not provide conclusions about association of the variant with Pheochromocytoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22703879). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (uncertain significance, n = 3; likely pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics	RCV003473253	SCV004202973	uncertain significance	Gastrointestinal stromal tumor	2024-03-11	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034687	SCV000043486	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004534728	SCV004120637	uncertain significance	SDHB-related disorder	2024-08-22	no assertion criteria provided	clinical testing	The SDHB c.403G>A variant is predicted to result in the amino acid substitution p.Val135Met. This variant was identified in an individual who underwent exome sequencing for atherosclerosis phenotypes (Table S1, Johnston et al. 2012. PubMed ID: 22703879), but to our knowledge, this variant has not been identified in individuals with cancer. This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. In ClinVar, this variant has conflicting interpretations of pathogenicity including likely benign, uncertain, and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/41770/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.