ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs1303837541
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.