Submissions for variant NM_000350.3(ABCA4):c.2915C>A (p.Thr972Asn)

dbSNP: rs61749451

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085523	SCV001218249	pathogenic	not provided	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 972 of the ABCA4 protein (p.Thr972Asn). This variant is present in population databases (rs61749451, gnomAD 0.007%). This missense change has been observed in individual(s) with Stargardt disease or retinitis pigmentosa (PMID: 28041643, 28559085, 29925512). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99174). 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%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV000504717	SCV001240215	likely pathogenic	Retinal dystrophy	2019-01-29	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000505078	SCV001950193	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Thr972Asn variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM1, PM2, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Fulgent Genetics, Fulgent Genetics	RCV002498454	SCV002805465	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2021-09-24	criteria provided, single submitter	clinical testing
Retina International	RCV000085523	SCV000117660	not provided	not provided		no assertion provided	not provided
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000505078	SCV000598954	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504717	SCV000598955	likely pathogenic	Retinal dystrophy	2015-01-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732666	SCV005362700	likely pathogenic	ABCA4-related disorder	2024-08-20	no assertion criteria provided	clinical testing	The ABCA4 c.2915C>A variant is predicted to result in the amino acid substitution p.Thr972Asn. This variant has been observed in individuals with Stargardt disease or ABCA4-related retinopathy (Bertelsen et al. 2014. PubMed ID: 24713488; Table S2; Carss et al. 2016. PubMed ID: 28041643; Areblom et al. 2023. PubMed ID: 37510321). It has been proposed to be a mild-to-moderate disease allele, in the compound heterozygous state (Table S2A, Cornelis et al. 2022. PubMed ID: 35120629). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.