ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.1156T>C (p.Trp386Arg)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000695581 SCV000893231 likely pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-10-31 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000790271 SCV000929674 uncertain significance Distal spinal muscular atrophy no assertion criteria provided literature only
Invitae RCV000695581 SCV000824090 pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 386 of the IGHMBP2 protein (p.Trp386Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs759641927, ExAC 0.005%). This variant has been reported in the compound heterozygous state with a second pathogenic IGHMBP2 variant in individuals affected with spinal muscular atrophy with respiratory distress (SMARD), Charcot-Marie-Tooth disease type 2 (CMT2), and with hereditary motor and sensory neuropathy (PMID: 17431882, 25439726, Invitae). In addition, this variant has been observed on the opposite chromosome (in trans) from other pathogenic IGHMBP2 variants in individuals affected with SMARD (PMID: 17431882). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. 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"). For these reasons, this variant has been classified as Pathogenic.

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