Submissions for variant NM_003000.3(SDHB):c.739A>G (p.Met247Val)

gnomAD frequency: 0.00002  dbSNP: rs200896502

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543096	SCV000630729	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-12-29	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 247 of the SDHB protein (p.Met247Val). This variant is present in population databases (rs200896502, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 32659967). ClinVar contains an entry for this variant (Variation ID: 459169). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. 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.
Ambry Genetics	RCV000575911	SCV000675066	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-14	criteria provided, single submitter	clinical testing	The p.M247V variant (also known as c.739A>G), located in coding exon 7 of the SDHB gene, results from an A to G substitution at nucleotide position 739. The methionine at codon 247 is replaced by valine, an amino acid with highly similar properties. In one study, this alteration was identified in a female patient diagnosed with high-grade vaginal fusocellular sarcoma and endometrial adenocarcinoma (de Angelis de Carvalho N et al. Cancers (Basel), 2020 Jul;12:). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237901	SCV002010040	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000575911	SCV002527091	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	curation
GeneDx	RCV003237901	SCV004036497	uncertain significance	not provided	2023-03-20	criteria provided, single submitter	clinical testing	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; Observed in an individual with vaginal fusocellular sarcoma and endometrial adenocarcinoma (de Angelis de Carvalho et al., 2020); This variant is associated with the following publications: (PMID: 32659967)
PreventionGenetics, part of Exact Sciences	RCV004537908	SCV004116372	uncertain significance	SDHB-related disorder	2023-06-14	criteria provided, single submitter	clinical testing	The SDHB c.739A>G variant is predicted to result in the amino acid substitution p.Met247Val. This variant has been reported in an individual with Lynch syndrome and sarcomas (Table S1, de Angelis de Carvalho et al. 2020. PubMed ID: 32659967). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-17349129-T-C). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/459169/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003476240	SCV004203009	uncertain significance	Gastrointestinal stromal tumor	2023-06-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003237901	SCV005075404	uncertain significance	not provided	2024-11-01	criteria provided, single submitter	clinical testing	SDHB: PM2