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
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.
Athena Diagnostics Inc	RCV000236185	SCV000613764	pathogenic	not provided	2016-11-02	criteria provided, single submitter	clinical testing
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.
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
Inherited Neuropathy Consortium	RCV000790269	SCV000929672	uncertain significance	Distal spinal muscular atrophy		no assertion criteria provided	literature only

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