Submissions for variant NM_003000.3(SDHB):c.638T>C (p.Met213Thr)

gnomAD frequency: 0.00001  dbSNP: rs202014362

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000462266	SCV000553982	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2023-09-04	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 213 of the SDHB protein (p.Met213Thr). This variant is present in population databases (rs202014362, gnomAD 0.01%). 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: 41771). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034689	SCV000698136	uncertain significance	not provided	2017-06-26	criteria provided, single submitter	clinical testing	Variant summary: The SDHB c.638T>C (p.Met213Thr) variant located in the alpha-helical ferredoxin domain (via InterPro) involves the alteration of a conserved nucleotide that 4/4 in silico tools predict a damaging outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 1/120790 control chromosomes at a frequency of 0.0000083, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic SDHB variant (0.0000009), suggesting this variant is likely a benign polymorphism. However, this is only one occurrence in a control population that could harbor individuals with a SDHB phenotype, therefore, this observation needs to be cautiously considered. In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Mendelics	RCV000708782	SCV000837730	uncertain significance	Cowden syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002354184	SCV002655296	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-13	criteria provided, single submitter	clinical testing	The p.M213T variant (also known as c.638T>C), located in coding exon 6 of the SDHB gene, results from a T to C substitution at nucleotide position 638. The methionine at codon 213 is replaced by threonine, an amino acid with similar properties. This variant was detected as a secondary finding in 1 out of 415 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (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.
Baylor Genetics	RCV003473254	SCV004202993	uncertain significance	Gastrointestinal stromal tumor	2023-08-25	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034689	SCV000043484	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.