Submissions for variant NM_005219.5(DIAPH1):c.1364G>A (p.Arg455Gln)

gnomAD frequency: 0.00006  dbSNP: rs200004048

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150405	SCV000197583	uncertain significance	not specified	2014-11-17	criteria provided, single submitter	clinical testing	The p.Arg455Gln variant in DIAPH1 has not been previously reported in individual s with hearing loss, but has been identified in 0.1% (1/1324) by ClinSeq project (dbSNP rs200004048). Although this variant has been seen in the general populat ion, its frequency is not high enough to rule out a pathogenic role. Computation al prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of th e p.Arg455Gln variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000652771	SCV000774642	uncertain significance	Autosomal dominant nonsyndromic hearing loss 1; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 455 of the DIAPH1 protein (p.Arg455Gln). This variant is present in population databases (rs200004048, gnomAD 0.006%). 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: 163074). 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.
PreventionGenetics, part of Exact Sciences	RCV003398797	SCV004119116	uncertain significance	DIAPH1-related disorder	2023-09-20	criteria provided, single submitter	clinical testing	The DIAPH1 c.1364G>A variant is predicted to result in the amino acid substitution p.Arg455Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-140956355-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Laboratory of Prof. Karen Avraham, Tel Aviv University	RCV004584612	SCV005073743	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 1	2024-05-06	criteria provided, single submitter	research	There are three submissions in ClinVar classified as VUS. As this is the 4th submission for impairments including HL of a rare variant predicted to cause damage, it is likely pathogenic.