Submissions for variant NM_000350.3(ABCA4):c.6221G>T (p.Gly2074Val)

dbSNP: rs367839100

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000850519	SCV000992723	likely pathogenic	Cone-rod dystrophy 3; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2018-10-12	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074418	SCV001240000	uncertain significance	Retinal dystrophy	2019-08-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001234782	SCV001407441	pathogenic	not provided	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2074 of the ABCA4 protein (p.Gly2074Val). This variant is present in population databases (rs367839100, gnomAD 0.03%). This missense change has been observed in individuals with Stargardt disease (PMID: 23419329, 25082885, 29925512; internal data). ClinVar contains an entry for this variant (Variation ID: 689736). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly2074 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 25412400), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262439	SCV001440312	uncertain significance	Cone-rod dystrophy 3	2019-01-01	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV002051899	SCV002318721	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2022-03-22	criteria provided, single submitter	clinical testing	A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001071049, PMID:25412400,18652558). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.994>=0.6, 3CNET: 0.996>=0.75). A missense variant is a common mechanism associated with Stargardt disease 1. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000358 ).Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV001234782	SCV005081186	likely pathogenic	not provided	2024-06-27	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: 23419329, 25082885, 29925512, 31736247, 25412400, 31216405, 31964843, 36087940, 35120629, 38347443)
PreventionGenetics, part of Exact Sciences	RCV004733063	SCV005356660	pathogenic	ABCA4-related disorder	2024-09-04	no assertion criteria provided	clinical testing	The ABCA4 c.6221G>T variant is predicted to result in the amino acid substitution p.Gly2074Val. This variant has been reported in the compound heterozygous state in several individuals with ABCA4-related retinal disease (Chacón-Camacho et al. 2013. PubMed ID: 23419329; Alapati et al. 2014. PubMed ID: 25082885; Table S1, Fujinami et al 2019. PubMed ID: 29925512; Zenteno et al. 2019. PubMed ID: 31736247). This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.