ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.188T>C (p.Val63Ala) (rs1230335211)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000547321 SCV000630695 uncertain significance Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2018-09-06 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 63 of the SDHB protein (p.Val63Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SDHB-related disease. 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. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001013468 SCV001174057 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-18 criteria provided, single submitter clinical testing The p.V63A variant (also known as c.188T>C), located in coding exon 2 of the SDHB gene, results from a T to C substitution at nucleotide position 188. The valine at codon 63 is replaced by alanine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357011 SCV001552334 uncertain significance not provided no assertion criteria provided clinical testing The SDHB p.Val63Ala variant was not identified in the literature nor was it identified in COSMIC or LOVD 3.0. The variant was also identified in dbSNP (ID:rs1230335211) and ClinVar (classified as a VUS by Invitae for Gastrointestinal stroma tumor, Paragangliomas 4 and Pheochromocytoma). The variant was identified in control databases in 1 of 251344 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: European (non-Finnish) in 1 of 113644 chromosomes (freq: 0.000009); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Val63 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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