Submissions for variant NM_004100.5(EYA4):c.1035G>C (p.Arg345Ser)

gnomAD frequency: 0.00045  dbSNP: rs140170914

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172547	SCV000051391	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000223647	SCV000271775	uncertain significance	not specified	2015-12-08	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg345Ser var iant in EYA4 has not been previously reported in individuals with hearing loss a nd has been identified in 0.1% (71/66610) of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140170914). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg345Ser variant is uncertain, frequency data suggest tha t it is more likely to be benign.
Illumina Laboratory Services, Illumina	RCV000340736	SCV000460385	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001085733	SCV000460386	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085733	SCV000561717	likely benign	Dilated cardiomyopathy 1J	2025-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000619332	SCV000736895	uncertain significance	Cardiovascular phenotype	2024-04-19	criteria provided, single submitter	clinical testing	The p.R345S variant (also known as c.1035G>C), located in coding exon 11 of the EYA4 gene, results from a G to C substitution at nucleotide position 1035. The arginine at codon 345 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet. 2013;6:337-46). This variant was also reported in a hearing loss cohort (Sommen M et al. Hum Mutat, 2016 Aug;37:812-9). This amino acid position is highly conserved in available vertebrate species. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000223647	SCV002571907	likely benign	not specified	2022-08-09	criteria provided, single submitter	clinical testing	Variant summary: EYA4 c.1035G>C (p.Arg345Ser) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 250806 control chromosomes, predominantly at a frequency of 0.00095 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 61-fold of the estimated maximal expected allele frequency for a pathogenic variant in EYA4 causing Dilated Cardiomyopathy phenotype (1.6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1035G>C has been reported in the literature in individuals from studies evaluating auditory and cardiovascular phenotypes (Ng_2013, Sommen_2016, Ahmadmehrabi_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=2) and as VUS (n=3) . Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000172547	SCV001927515	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000172547	SCV001954390	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172547	SCV001972226	likely benign	not provided		no assertion criteria provided	clinical testing