ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.482A>G (p.Asp161Gly) (rs1049317868)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564159 SCV000664677 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-31 criteria provided, single submitter clinical testing The p.D161G variant (also known as c.482A>G), located in coding exon 5 of the SDHB gene, results from an A to G substitution at nucleotide position 482. The aspartic acid at codon 161 is replaced by glycine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 20000 alleles tested) in our clinical cohort. 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 RCV000803790 SCV000943676 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-07-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 161 of the SDHB protein (p.Asp161Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 480839). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV001194403 SCV001363920 uncertain significance not specified 2019-06-28 criteria provided, single submitter clinical testing Variant summary: SDHB c.482A>G (p.Asp161Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251372 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.482A>G has been reported in the literature as a somatic occurrence in an individual affected with a gastrointestinal stromal tumor (GIST) (Shi_2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Paraganglioma-Pheochromocytoma Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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