Submissions for variant NM_005219.5(DIAPH1):c.2107C>G (p.Pro703Ala)

gnomAD frequency: 0.00015  dbSNP: rs201433617

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219307	SCV000271648	uncertain significance	not specified	2015-08-21	criteria provided, single submitter	clinical testing	The p.Pro703Ala variant has not been previously reported in individuals with hea ring loss, but has been identified in 14/32612 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201433617 ). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impac t to the protein. In summary, the clinical significance of the p.Pro703Ala varia nt is uncertain.
Invitae	RCV000806173	SCV000946158	uncertain significance	Autosomal dominant nonsyndromic hearing loss 1; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 703 of the DIAPH1 protein (p.Pro703Ala). This variant is present in population databases (rs201433617, gnomAD 0.03%). 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: 228575). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	RCV001723797	SCV002756777	uncertain significance	not provided	2022-11-17	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	RCV002517539	SCV003692851	likely benign	Inborn genetic diseases	2022-03-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723797	SCV001955520	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723797	SCV001974967	likely benign	not provided		no assertion criteria provided	clinical testing