ClinVar Miner

Submissions for variant NM_005219.5(DIAPH1):c.2158C>T (p.Leu720Phe)

gnomAD frequency: 0.00042  dbSNP: rs200606811
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001722443 SCV000619016 likely benign not provided 2020-07-21 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000519502 SCV000731530 likely benign not specified 2017-02-28 criteria provided, single submitter clinical testing p.Leu720Phe in exon 16 of DIAPH1: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note,4 mammals (rat, mouse, Tibetan antelope, and shrew) have a phenylalanine ( Phe) at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has been identified in 5/6746 Latino chromosomes and 4/7384 African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs200606811).
Invitae RCV000652763 SCV000774634 uncertain significance Autosomal dominant nonsyndromic hearing loss 1; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 720 of the DIAPH1 protein (p.Leu720Phe). This variant is present in population databases (rs200606811, gnomAD 0.1%). 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: 450432). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The phenylalanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV002525173 SCV003622457 likely benign Inborn genetic diseases 2022-07-21 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.

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