Submissions for variant NM_000350.3(ABCA4):c.2966T>C (p.Val989Ala)

gnomAD frequency: 0.00089  dbSNP: rs61749454

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085529	SCV000321347	pathogenic	not provided	2024-09-18	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: 15161829, 22863181, 19406377, 35120629, 31964843, 32307445, 32531858, 11328725, 14517951, 25066811, 16123440, 12397427, 29126757, 29925512, 24550365, 28327576, 31980526, 32581362, 35119454, 35076026, 22247458, 11527935)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085529	SCV001202798	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 989 of the ABCA4 protein (p.Val989Ala). This variant is present in population databases (rs61749454, gnomAD 0.3%). This missense change has been observed in individual(s) with ABCA4-related retinal disease (PMID: 22247458, 23755871, 25066811, 28327576; Invitae). 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: 99180). 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 ABCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.Val989 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 29641573), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074424	SCV001240007	pathogenic	Retinal dystrophy	2019-08-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085529	SCV001249472	pathogenic	not provided	2018-09-01	criteria provided, single submitter	clinical testing
Retina International	RCV000085529	SCV000117666	not provided	not provided		no assertion provided	not provided
Eurofins Ntd Llc (ga)	RCV000085529	SCV000339698	uncertain significance	not provided	2016-02-22	flagged submission	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504904	SCV000598956	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2015-01-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732667	SCV005366944	pathogenic	ABCA4-related disorder	2024-09-06	no assertion criteria provided	clinical testing	The ABCA4 c.2966T>C variant is predicted to result in the amino acid substitution p.Val989Ala. This variant has been reported many times in the compound heterozygous state in individuals with Stargardt disease or ABCA4-related retinal disease (see for examples Briggs et al. 2001. PubMed ID: 11527935; Cideciyan et al. 2012. PubMed ID: 22247458; Lee et al. 2017. PubMed ID: 28327576). This variant is relatively common in some populations, with the highest allele frequency being 0.30% in individuals of African descent as reported in gnomAD. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99180/). Given all the evidence, we too interpret c.2966T>C (p.Val989Ala) as pathogenic.