Submissions for variant NM_005219.5(DIAPH1):c.217G>A (p.Ala73Thr)

gnomAD frequency: 0.00006  dbSNP: rs184081055

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000697821	SCV000826452	uncertain significance	Autosomal dominant nonsyndromic hearing loss 1; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 73 of the DIAPH1 protein (p.Ala73Thr). This variant is present in population databases (rs184081055, gnomAD 0.01%). 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: 575565). 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 threonine 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.
Illumina Laboratory Services, Illumina	RCV001151822	SCV001312993	uncertain significance	Autosomal dominant nonsyndromic hearing loss 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001536492	SCV001753259	uncertain significance	not provided	2020-09-11	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002533501	SCV003528243	uncertain significance	Inborn genetic diseases	2021-06-18	criteria provided, single submitter	clinical testing	The c.217G>A (p.A73T) alteration is located in exon 3 (coding exon 3) of the DIAPH1 gene. This alteration results from a G to A substitution at nucleotide position 217, causing the alanine (A) at amino acid position 73 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.