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

Total submissions: 5

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.