Submissions for variant NM_002180.3(IGHMBP2):c.761G>A (p.Arg254His)

gnomAD frequency: 0.00005  dbSNP: rs761191746

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235714	SCV000294155	uncertain significance	not provided	2016-05-11	criteria provided, single submitter	clinical testing	The R254H variant has has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R254H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and missense variants in nearby residues (L251P; A256G) have been reported in the Human Gene Mutation Database in association with IGHMBP2-related disorders (Stenson et al., 2014). Additionally, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000696905	SCV000825486	uncertain significance	Autosomal recessive distal spinal muscular atrophy 1; Charcot-Marie-Tooth disease axonal type 2S	2022-06-22	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 254 of the IGHMBP2 protein (p.Arg254His). This variant is present in population databases (rs761191746, gnomAD 0.006%). 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: 246563). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000790913	SCV000930160	uncertain significance	not specified	2019-04-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000235714	SCV002049020	uncertain significance	not provided	2021-02-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002392735	SCV002668818	uncertain significance	Inborn genetic diseases	2020-12-08	criteria provided, single submitter	clinical testing	The p.R254H variant (also known as c.761G>A), located in coding exon 6 of the IGHMBP2 gene, results from a G to A substitution at nucleotide position 761. The arginine at codon 254 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.