ClinVar Miner

Submissions for variant NM_002180.3(IGHMBP2):c.1156T>C (p.Trp386Arg)

gnomAD frequency: 0.00002  dbSNP: rs759641927
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000695581 SCV000824090 pathogenic Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S 2023-11-04 criteria provided, single submitter clinical testing This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 386 of the IGHMBP2 protein (p.Trp386Arg). This variant is present in population databases (rs759641927, gnomAD 0.006%). This missense change has been observed in individual(s) 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 at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 573815). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IGHMBP2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000695581 SCV000893231 likely pathogenic Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S 2018-10-31 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001784325 SCV002016695 likely pathogenic not provided 2020-02-26 criteria provided, single submitter clinical testing
Baylor Genetics RCV003147534 SCV003834876 pathogenic Autosomal recessive distal spinal muscular atrophy 1 2021-03-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV003243261 SCV003953020 likely pathogenic Inborn genetic diseases 2023-06-07 criteria provided, single submitter clinical testing The c.1156T>C (p.W386R) alteration is located in exon 8 (coding exon 8) of the IGHMBP2 gene. This alteration results from a T to C substitution at nucleotide position 1156, causing the tryptophan (W) at amino acid position 386 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.002% (7/282524) total alleles studied. The highest observed frequency was 0.005% (6/129074) of European (non-Finnish) alleles. This alteration was detected in conjunction with another alteration in IGHMBP2, in multiple individuals with features of IGHMBP2-related neuropathy (Kulshrestha, 2018; Cottenie, 2014; Guenther, 2007). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Inherited Neuropathy Consortium RCV000790271 SCV000929674 uncertain significance Distal spinal muscular atrophy no assertion criteria provided literature only
Genesis Genome Database RCV000790271 SCV000999534 uncertain significance Distal spinal muscular atrophy 2019-08-14 no assertion criteria provided research

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