ClinVar Miner

Submissions for variant NM_001378457.1(DMXL2):c.8219G>A (p.Arg2740His)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002761565 SCV003023263 uncertain significance not provided 2022-05-17 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 2719 of the DMXL2 protein (p.Arg2719His). This variant is present in population databases (rs367772050, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DMXL2-related conditions. 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: "Tolerated"; PolyPhen-2: "Probably 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.
King Laboratory, University of Washington RCV003155490 SCV003844154 likely pathogenic Hearing loss, autosomal dominant 71 2023-02-28 criteria provided, single submitter research This variant occurred in heterozygosity in multiple patients with bilateral sensorineural hearing loss of onset <18 years within a single family, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). Affected individuals in this family include three siblings, their mother, and their maternal grandmother. All have a similar hearing loss phenotype. This variant is a missense at a completely conserved site and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has not been reported to ClinVar and is found in 21 heterozygotes on gnomAD. Based on consistently predicted functional effect, co-segregation with the phenotype within the family, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.

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