Submissions for variant NM_152443.3(RDH12):c.377C>T (p.Ala126Val)

gnomAD frequency: 0.00001  dbSNP: rs202126574

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001073666	SCV001239218	pathogenic	Retinal dystrophy	2019-08-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001223788	SCV001395952	pathogenic	Leber congenital amaurosis 13	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 126 of the RDH12 protein (p.Ala126Val). This variant is present in population databases (rs202126574, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive RDH12-related disease (PMID: 19140180, 30134391). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2061). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RDH12 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001558134	SCV001780019	likely pathogenic	not provided	2024-05-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19140180, 24752437, 26667666, 26261414, 31980526, 31054281, 31456290, 33090715, 33629268, 35006499, 31630094, 33691693, 30134391)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155010	SCV003844332	pathogenic	Leber congenital amaurosis	2023-02-28	criteria provided, single submitter	clinical testing	Variant summary: RDH12 c.377C>T (p.Ala126Val) results in a non-conservative amino acid change in 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 1.2e-05 in 251476 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.377C>T has been reported in the literature in multiple individuals affected with Leber Congenital Amaurosis (e.g., Kuniyoshi_2014, Sharon_2015, Benayoun_2009, Aleman_2018), and the variant was found to segregate with disease in multiple unrelated families. These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic (n = 3) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001223788	SCV004208562	pathogenic	Leber congenital amaurosis 13	2024-03-09	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV001073666	SCV004707751	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
OMIM	RCV000002142	SCV000022300	pathogenic	Retinitis pigmentosa 53	2009-02-15	no assertion criteria provided	literature only
Department of Ophthalmology and Visual Sciences Kyoto University	RCV000132691	SCV000172644	pathogenic	Retinitis pigmentosa		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000132691	SCV001161224	pathogenic	Retinitis pigmentosa	2019-06-23	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004734494	SCV005362511	pathogenic	RDH12-related disorder	2024-09-25	no assertion criteria provided	clinical testing	The RDH12 c.377C>T variant is predicted to result in the amino acid substitution p.Ala126Val. This variant was reported in an individual with RDH12-related retinal disease (see for examples, Benayoun et al. 2009. PubMed ID: 19140180; Supplemental data 1, Chen et al. 2021. PubMed ID: 33608557). A variant at the same amino acid position has also been found to be pathogenic for RDH12-related retinal disease (p.Ala126Glu, Supplementary table 1, Stone et al. 2017. PubMed ID: 28559085). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.