ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.2176G>A (p.Val726Met) (rs143986510)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726111 SCV000342052 uncertain significance not provided 2016-06-03 criteria provided, single submitter clinical testing
GeneDx RCV000726111 SCV000292590 uncertain significance not provided 2019-01-09 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the IGHMBP2 gene. The V726M variant hasnot been published as a pathogenic variant, nor has it been reported as a benign variant to ourknowledge. The V726M variant is observed in 30/30774 (0.1%) alleles from individuals of South Asianbackground in large population cohorts (Lek et al., 2016). The V726M variant is a conservativeamino acid substitution, which is not likely to impact secondary protein structure as these residuesshare similar properties. In-silico analyses, including protein predictors and evolutionary conservation,support that this variant does not alter protein structure/function. Based on the currently availableinformation, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000532649 SCV000642334 uncertain significance Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 726 of the IGHMBP2 protein (p.Val726Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs143986510, ExAC 0.09%). This variant has not been reported in the literature in individuals with IGHMBP2-related disease. ClinVar contains an entry for this variant (Variation ID: 245631). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.

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