Submissions for variant NM_000717.5(CA4):c.415A>T (p.Met139Leu)

gnomAD frequency: 0.00009  dbSNP: rs185658468

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000366585	SCV000404390	likely benign	Retinitis pigmentosa	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757049	SCV000885132	uncertain significance	not provided	2018-06-04	criteria provided, single submitter	clinical testing	The CA4 c.415A>T; p.Met139Leu variant (rs185658468) is not reported in the medical literature or in gene-specific databases. The variant is reported in the ClinVar database (Variation ID: 324231) and in the Genome Aggregation Database in 0.4% (77/18868 alleles) in the East Asian population and in 0.03% (85/2771900 alleles) overall. The methionine at codon 139 is weakly conserved across species and computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Additionally, this variant occurs in the first nucleotide of the exon and computational algorithms predict there is a small chance this variant alters mRNA splicing (Alamut v.2.11.0). Considering available information, there is insufficient evidence to classify this variant with certainty. Pathogenic CA4 variants are causative for autosomal dominant retinitis pigmentosa (MIM: 600852).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000757049	SCV001033052	likely benign	not provided	2023-12-22	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV003888774	SCV004706213	benign	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
PreventionGenetics, part of Exact Sciences	RCV003940282	SCV004751482	benign	CA4-related disorder	2019-05-28	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).