ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.791G>T (p.Arg264Leu) (rs777575504)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000541500 SCV000642369 likely pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 264 of the IGHMBP2 protein (p.Arg264Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs777575504, ExAC 0.006%). This variant has been reported in individuals affected with Charcot-Marie-Tooth (CMT) disease type 2 (PMID: 26392352). This variant occurs with a likely pathogenic variant (p.Val580ILe) in IGHMBP2 in an individual affected with CMT (Invitae). Family studies indicate these two variants are on opposite chromosomes (in trans), which suggests the c.791G>T substitution may contribute to disease. ClinVar contains an entry for this variant (Variation ID: 466598). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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