ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.1082T>C (p.Leu361Pro) (rs201060167)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000236185 SCV000613764 pathogenic not provided 2016-11-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000544728 SCV000893230 pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000236185 SCV000292586 pathogenic not provided 2018-03-14 criteria provided, single submitter clinical testing The L361P pathogenic variant in the IGHMBP2 gene has been reported previously in association with SMARD1 in multiple individuals who harbor a second pathogenic variant on the opposite IGHMBP2 allele (Pitt et al., 2003, Guenther et al., 2007; Guenther et al., 2009). The L361P variant is observed in 7/66,618 (0.01%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution occurs at a position that is conserved across species.
Inherited Neuropathy Consortium RCV000790269 SCV000929672 uncertain significance Distal spinal muscular atrophy no assertion criteria provided literature only
Invitae RCV000544728 SCV000642295 pathogenic Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 361 of the IGHMBP2 protein (p.Leu361Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs201060167, ExAC 0.01%). This variant has been reported in multiple individual with spinal muscular atrophy with respiratory distress type 1 as compound heterozygous with other loss-of-function or missense variants in IGHMBP2 gene (PMID: 14506069, 14681881) and in an individual with distal spinal muscular atrophy type 1 segregating with disease (PMID: 18802676). ClinVar contains an entry for this variant (Variation ID: 245627). Experimental evidence suggests that this variant results in a IGHMBP2 protein with loss of enzyme activity (PMID: 22157136). For these reasons, this variant has been classified as Pathogenic.

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