ClinVar Miner

Submissions for variant NM_001378457.1(DMXL2):c.7250G>A (p.Arg2417His)

gnomAD frequency: 0.00003  dbSNP: rs754786373
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002524064 SCV003442948 uncertain significance not provided 2022-01-31 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 2417 of the DMXL2 protein (p.Arg2417His). This variant is present in population databases (rs754786373, gnomAD 0.008%). This missense change has been observed in individual(s) with autosomal dominant non-syndromic hearing loss (PMID: 27657680). ClinVar contains an entry for this variant (Variation ID: 431430). 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: "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 RCV000496988 SCV003844155 likely pathogenic Hearing loss, autosomal dominant 71 2023-02-28 criteria provided, single submitter research This variant occurred in heterozygosity in a patient 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). This patient’s family has no other history of hearing loss. 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 been reported to ClinVar as likely pathogenic and is found in 9 heterozygotes on gnomAD. Based on consistently predicted functional effect, literature evidence of pathogenicity, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.
OMIM RCV000496988 SCV000588220 pathogenic Hearing loss, autosomal dominant 71 2021-05-05 no assertion criteria provided literature only

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