Submissions for variant NM_002180.3(IGHMBP2):c.791G>A (p.Arg264His)

dbSNP: rs777575504

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700554	SCV000829313	pathogenic	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 264 of the IGHMBP2 protein (p.Arg264His). This variant is present in population databases (rs777575504, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of IGHMBP2-related conditions (PMID: 28902413; Invitae). ClinVar contains an entry for this variant (Variation ID: 577730). 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.Arg264 amino acid residue in IGHMBP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26392352; Invitae). 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.
Ambry Genetics	RCV002422564	SCV002676955	uncertain significance	Inborn genetic diseases	2021-06-30	criteria provided, single submitter	clinical testing	The p.R264H variant (also known as c.791G>A), located in coding exon 6 of the IGHMBP2 gene, results from a G to A substitution at nucleotide position 791. The arginine at codon 264 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in an individual with suspected hereditary neuropathy, who also had another variant in IGHMBP2; however, clinical details were limited, and it was unclear if the variants were in cis or trans (Dohrn MF et al. J Neurochem, 2017 12;143:507-522). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV003133554	SCV003813300	uncertain significance	not provided	2019-04-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800546	SCV005423434	uncertain significance	not specified	2024-10-04	criteria provided, single submitter	clinical testing	Variant summary: IGHMBP2 c.791G>A (p.Arg264His) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251468 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.791G>A has been reported in the literature in a heterozygous individual affected with Charcot-Marie-Tooth disease axonal type 2S (Dohrn_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28902413). ClinVar contains an entry for this variant (Variation ID: 577730). Based on the evidence outlined above, the variant was classified as uncertain significance.
GenomeConnect - Invitae Patient Insights Network	RCV000700554	SCV001749813	not provided	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S		no assertion provided	phenotyping only	Variant interpreted as Likely pathogenic and reported on 11-24-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.