Submissions for variant NM_174878.3(CLRN1):c.183G>A (p.Met61Ile)

gnomAD frequency: 0.00012  dbSNP: rs140094683

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000598081	SCV000708387	uncertain significance	not provided	2017-05-17	criteria provided, single submitter	clinical testing
Invitae	RCV000598081	SCV001198549	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 61 of the CLRN1 protein (p.Met61Ile). This variant is present in population databases (rs140094683, gnomAD 0.03%). 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: 501869). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine 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	RCV001146711	SCV001307465	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.
Genome-Nilou Lab	RCV001275854	SCV001781375	uncertain significance	Usher syndrome type 3A	2021-07-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003160054	SCV003876550	uncertain significance	Inborn genetic diseases	2023-02-22	criteria provided, single submitter	clinical testing	The c.183G>A (p.M61I) alteration is located in exon 1 (coding exon 1) of the CLRN1 gene. This alteration results from a G to A substitution at nucleotide position 183, causing the methionine (M) at amino acid position 61 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001275854	SCV001461432	uncertain significance	Usher syndrome type 3A	2020-06-04	no assertion criteria provided	clinical testing