ClinVar Miner

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

gnomAD frequency: 0.00012  dbSNP: rs201585157
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Total submissions: 8
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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.
Invitae 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 likely pathogenic not provided 2023-03-06 criteria provided, single submitter clinical testing Observed in several heterozygous clinically unaffected adult relatives of individuals referred for genetic testing at GeneDx; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge; This variant has only been reported/observed in association with autosomal recessive complex II deficiency and has not, to our knowledge, been associated with autosomal dominant hereditary paraganglioma/pheochromocytoma syndrome; 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.
PreventionGenetics, part of Exact Sciences RCV004534728 SCV004120637 uncertain significance SDHB-related disorder 2023-07-11 criteria provided, single submitter clinical testing The SDHB c.403G>A variant is predicted to result in the amino acid substitution p.Val135Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-17355115-C-T). In ClinVar, this variant is classified as uncertain (3) and likely pathogenic (1) (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.
Baylor Genetics RCV003473253 SCV004202973 uncertain significance Gastrointestinal stromal tumor 2023-10-16 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.

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