Submissions for variant NM_002180.3(IGHMBP2):c.1273C>T (p.Arg425Cys)

gnomAD frequency: 0.00001  dbSNP: rs1303837541

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000806743	SCV000946758	pathogenic	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 425 of the IGHMBP2 protein (p.Arg425Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of IGHMBP2-related conditions (PMID: 22791546, 30598237, 30863264, 32573669). ClinVar contains an entry for this variant (Variation ID: 637695). 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%. This variant disrupts the p.Arg425 amino acid residue in IGHMBP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33258288). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000853264	SCV000996092	likely pathogenic	Autosomal recessive distal spinal muscular atrophy 1	2017-12-19	criteria provided, single submitter	clinical testing	This variant was previously reported in a compound heterozygous state in an infant with infantile spinal muscular atrophy with respiratory distress type 1 (PMID: 22791546). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0012% (3/246146). This variant has not been functionally characterized to our knowledge. However, multiple in silico analysis predict the variant to be damaging. Based on the combined evidence, the p.Gly260Arg variant is classified as likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000853264	SCV001245042	pathogenic	Autosomal recessive distal spinal muscular atrophy 1	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth disease, axonal, type 2S (MIM#616155), and distal hereditary motor neuronopathy, type VI (MIM#604320). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 3 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (Highest allele count v2: 6 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated 1A region of the DNA helicase domain (PMID: 30598237). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(Arg425His) has been reported as a VUS (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS, likely pathogenic and pathogenic (ClinVar). It has been observed in multiple compound heterozygous individuals and a single homozygous individual with spinal muscular atrophy and respiratory distress (PMID: 22791546, 30863264, 30598237, 28765793). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_002180.2(IGHMBP2):c.1488C>A; p.(Cys496*)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000789974	SCV001336676	uncertain significance	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003489865	SCV004238247	likely pathogenic	not provided	2023-06-12	criteria provided, single submitter	clinical testing
Inherited Neuropathy Consortium	RCV000789974	SCV000929363	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only