Submissions for variant NM_004100.5(EYA4):c.860C>T (p.Ala287Val)

gnomAD frequency: 0.00003  dbSNP: rs374522988

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051621	SCV001215787	uncertain significance	Dilated cardiomyopathy 1J	2022-10-15	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EYA4 protein function. ClinVar contains an entry for this variant (Variation ID: 847971). This variant has not been reported in the literature in individuals affected with EYA4-related conditions. This variant is present in population databases (rs374522988, gnomAD 0.02%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 287 of the EYA4 protein (p.Ala287Val).
Illumina Laboratory Services, Illumina	RCV001152684	SCV001313910	uncertain significance	Autosomal dominant nonsyndromic hearing loss 10	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.
Illumina Laboratory Services, Illumina	RCV001051621	SCV001315270	uncertain significance	Dilated cardiomyopathy 1J	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	RCV001759784	SCV002006977	uncertain significance	not provided	2020-10-27	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	RCV002445271	SCV002681413	uncertain significance	Cardiovascular phenotype	2023-10-27	criteria provided, single submitter	clinical testing	The p.A287V variant (also known as c.860C>T), located in coding exon 10 of the EYA4 gene, results from a C to T substitution at nucleotide position 860. The alanine at codon 287 is replaced by valine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002479320	SCV002782791	uncertain significance	Dilated cardiomyopathy 1J; Autosomal dominant nonsyndromic hearing loss 10	2021-10-01	criteria provided, single submitter	clinical testing