ClinVar Miner

Submissions for variant NM_005219.5(DIAPH1):c.3051G>A (p.Met1017Ile)

gnomAD frequency: 0.00009  dbSNP: rs373275414
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Total submissions: 4
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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 RCV000613351 SCV000711015 uncertain significance not specified 2016-06-02 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Met1017Ile va riant in DIAPH1 has not been previously reported in individuals with hearing los s. This variant has been identified in 1/9804 African chromosomes and 1/11576 o f Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs373275414). Although this variant has been seen in the g eneral population, its frequency is not high enough to rule out a pathogenic rol e. Computational prediction tools and conservation analyses suggest that this va riant may not impact the protein, though this information is not predictive enou gh to rule out pathogenicity. In summary, while the clinical significance of the p.Met1017Ile variant is uncertain, the computational and conservation data sugg est that it is more likely to be benign.
Invitae RCV000808089 SCV000948180 uncertain significance Autosomal dominant nonsyndromic hearing loss 1; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome 2023-10-05 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1017 of the DIAPH1 protein (p.Met1017Ile). This variant is present in population databases (rs373275414, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 504567). 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 RCV002260651 SCV002540548 uncertain significance not provided 2022-06-27 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 RCV003243213 SCV003951347 uncertain significance Inborn genetic diseases 2023-05-17 criteria provided, single submitter clinical testing The c.3051G>A (p.M1017I) alteration is located in exon 23 (coding exon 23) of the DIAPH1 gene. This alteration results from a G to A substitution at nucleotide position 3051, causing the methionine (M) at amino acid position 1017 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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