Submissions for variant NM_001298.3(CNGA3):c.1585G>A (p.Val529Met)

gnomAD frequency: 0.00004  dbSNP: rs104893619

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000352391	SCV000329302	pathogenic	not provided	2021-12-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect, however additional studies are needed to validate the functional effect of this variant in vivo (Muraki-Oda et al., 2007); This variant is associated with the following publications: (PMID: 26992781, 31456290, 9662398, 15712225, 20549516, 17693388)
CeGaT Center for Human Genetics Tuebingen	RCV000352391	SCV001249388	pathogenic	not provided	2016-10-01	criteria provided, single submitter	clinical testing
Invitae	RCV000352391	SCV001394270	pathogenic	not provided	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 529 of the CNGA3 protein (p.Val529Met). This variant is present in population databases (rs104893619, gnomAD 0.03%). This missense change has been observed in individual(s) with achromatopsia or inherited retinal dystrophy (PMID: 9662398, 15712225, 20549516, 24903488). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9480). 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 CNGA3 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CNGA3 function (PMID: 17693388). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000010088	SCV001451658	pathogenic	Achromatopsia 2	2020-06-05	criteria provided, single submitter	clinical testing	The CNGA3 c.1585G>A (p.Val529Met) variant is a missense variant that has been reported in at least four studies, in which it was found in at least 14 unrelated individuals with achromatopsia, including nine in a homozygous state and five in a compound heterozygous state (Kohl et al. 1998; Wissinger et al. 2001; Nishiguchi et al. 2005; Zelinger et al. 2010). The p.Val529Met variant was absent from 190 controls but is reported at a frequency of 0.000301 in the East Asian population from the Genome Aggregation Database. In patch-clamp studies of HEK293 cells transfected with p.Val529Met variant cDNA, no cGMP-activated current was observed (Muraki-Oda et al. 2007). Based on the collective evidence and application of the ACMG criteria, the p.Val529Met variant is classified as pathogenic for achromatopsia.
OMIM	RCV000010088	SCV000030309	pathogenic	Achromatopsia 2	2010-09-01	no assertion criteria provided	literature only
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002968	SCV001161016	pathogenic	Achromatopsia	2019-06-23	no assertion criteria provided	research