Submissions for variant NM_174878.3(CLRN1):c.473A>G (p.Glu158Gly)

gnomAD frequency: 0.00001  dbSNP: rs369185342

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000327197	SCV000441713	uncertain significance	Usher syndrome type 3	2018-01-13	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	RCV001338770	SCV001532464	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 158 of the CLRN1 protein (p.Glu158Gly). This variant is present in population databases (rs369185342, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CLRN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 343817). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001338770	SCV001799713	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001338770	SCV001976191	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000327197	SCV002081529	uncertain significance	Usher syndrome type 3	2020-05-13	no assertion criteria provided	clinical testing