ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.638T>C (p.Met213Thr) (rs202014362)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000462266 SCV000553982 uncertain significance Gastrointestinal stroma tumor; Paragangliomas 4; Pheochromocytoma 2018-03-06 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 213 of the SDHB protein (p.Met213Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs202014362, ExAC 0.01%). This variant has not been reported in the literature in individuals with SDHB-related disease. ClinVar contains an entry for this variant (Variation ID: 41771). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Mendelics RCV000708782 SCV000837730 uncertain significance Cowden syndrome 2018-07-02 criteria provided, single submitter clinical testing

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