ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs202014362
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Total submissions: 7
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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
All of Us Research Program, National Institutes of Health RCV003996176 SCV004816020 uncertain significance Hereditary pheochromocytoma-paraganglioma 2023-08-15 criteria provided, single submitter clinical testing This missense variant replaces methionine with threonine at codon 213 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with pheochromocytoma/paraganglioma in the literature but has been identified in an individual without cancer (PMID: 22703879). This variant has been identified in 2/251328 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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.

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