Submissions for variant NM_002180.3(IGHMBP2):c.2540del (p.Gln847fs)

dbSNP: rs1225532037

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204582	SCV001375795	pathogenic	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln847Argfs*131) in the IGHMBP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 147 amino acid(s) of the IGHMBP2 protein. This variant is present in population databases (no rsID available, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with IGHMBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 935895). This variant disrupts a region of the IGHMBP2 protein in which other variant(s) (p.Arg971Glufs*4, p.Lys868Profs*109) have been determined to be pathogenic (PMID: 23566544, 26298607). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genetics Laboratory, Department of Biology, Semnan University	RCV002271630	SCV002555592	pathogenic	Charcot-Marie-Tooth disease axonal type 2S	2019-04-22	criteria provided, single submitter	case-control	The WES analysis identified a frameshift mutation in the IGHMBP2 gene on chromosome11 (NM_002180.3); chr11:68937020delA c.2540delA: p.Q847fs. The mutation was predicted to be pathogenic based on ACMG guidelines. Our review of the public resources, local population database, and the literature revealed that there is no previous publication describing this mutation.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV002285021	SCV002574838	likely pathogenic	Autosomal recessive distal spinal muscular atrophy 1	2022-09-22	criteria provided, single submitter	clinical testing
GeneDx	RCV002285454	SCV002575361	likely pathogenic	not provided	2022-09-16	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 147 amino acids are replaced with 130 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV002285454	SCV002818220	pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing