Submissions for variant NM_022772.4(EPS8L2):c.1584G>C (p.Trp528Cys)

gnomAD frequency: 0.00137  dbSNP: rs184903112

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002001587	SCV002269507	uncertain significance	not provided	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 528 of the EPS8L2 protein (p.Trp528Cys). This variant is present in population databases (rs184903112, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with EPS8L2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1489788). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV002001587	SCV003936779	uncertain significance	not provided	2023-01-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in apparent homozygous state in unrelated healthy adult individuals tested at GeneDx; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317568	SCV004021195	uncertain significance	not specified	2023-06-05	criteria provided, single submitter	clinical testing	Variant summary: EPS8L2 c.1584G>C (p.Trp528Cys) results in a non-conservative amino acid change located in the SH3 domain (IPR001452) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 150904 control chromosomes (gnomAD v3.1.2). To our knowledge, no occurrence of c.1584G>C in individuals affected with Hearing Loss, Autosomal Recessive 106 and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003444978	SCV004171602	uncertain significance	Hearing loss, autosomal recessive 106	2023-11-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003958460	SCV004783021	likely benign	EPS8L2-related disorder	2022-09-23	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).