ClinVar Miner

Submissions for variant NM_005219.5(DIAPH1):c.3050T>C (p.Met1017Thr)

gnomAD frequency: 0.00043  dbSNP: rs376220834
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000155084 SCV000204768 uncertain significance not specified 2014-04-11 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Met1017Thr vari ant in DIAPH1 has not been previously reported in individuals with hearing loss. It was identified in 0.025% (1/4022) of African American chromosomes by the NHL BI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). The methionine (Met) at position 1017 is conserved in mammals, but not in birds or evolutionari ly distant species, with many bird species having a threonine. This raises the possibility that a change at this position may be tolerated. In summary, while t he clinical significance of the Met1017Thr variant is uncertain, these data sugg est that it is more likely to be benign.
Labcorp Genetics (formerly Invitae), Labcorp RCV000694570 SCV000823021 uncertain significance Autosomal dominant nonsyndromic hearing loss 1; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome 2025-01-23 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1017 of the DIAPH1 protein (p.Met1017Thr). This variant is present in population databases (rs376220834, gnomAD 0.1%). This missense change has been observed in individual(s) with a developmental disorder (PMID: 33057194). ClinVar contains an entry for this variant (Variation ID: 178340). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
GeneDx RCV002464130 SCV002759283 uncertain significance not provided 2022-11-30 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics RCV002516119 SCV003717585 likely benign Inborn genetic diseases 2022-08-12 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Mayo Clinic Laboratories, Mayo Clinic RCV002464130 SCV005411881 uncertain significance not provided 2024-05-04 criteria provided, single submitter clinical testing BP5

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