ClinVar Miner

Submissions for variant NM_002180.2(IGHMBP2):c.2753G>A (p.Arg918His) (rs368584364)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000323396 SCV000373806 uncertain significance Spinal muscular atrophy, distal, autosomal recessive, 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000506964 SCV000604017 uncertain significance not provided 2017-05-02 criteria provided, single submitter clinical testing The p.Arg918His variant (rs368584364) has not been reported in the medical literature, nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 305860). It is listed in the NHLBI GO Exome Sequencing Project (ESP) with an overall allele frequency of 0.008% (identified in 1 out of 12,976 chromosomes), and in the Exome Aggregation Consortium (ExAC) browser with an overall frequency of 0.007% (identified in 7 out of 105,500 chromosomes). The arginine at codon 918 is moderately conserved considering 11 species (Alamut software v2.8.1), and computational analyses suggest this variant does not have a significant effect on IGHMBP2 protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Arg918His variant cannot be determined with certainty.
Invitae RCV001070291 SCV001235513 uncertain significance Spinal muscular atrophy, distal, autosomal recessive, 1; Charcot-Marie-Tooth disease, axonal, type 2S 2020-06-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 918 of the IGHMBP2 protein (p.Arg918His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs368584364, ExAC 0.02%). This variant has not been reported in the literature in individuals with IGHMBP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 305860). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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