Submissions for variant NM_000350.3(ABCA4):c.2401G>A (p.Ala801Thr)

gnomAD frequency: 0.00001  dbSNP: rs374410829

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778261	SCV000914433	uncertain significance	ABCA4-Related Disorders	2018-11-07	criteria provided, single submitter	clinical testing	The ABCA4 c.2401G>A (p.Ala801Thr) missense variant has been reported in a compound heterozygous state with as second missense variant in one individual with an unspecified ABCA4-related disorder (Zernant et al. 2011). This variant has also been found in an individual with unspecified retinal degeneration, although with unknown zygosity (Downs et al. 2007). The p.Ala801Thr variant was absent from 100 control chromosomes and is reported at a frequency of 0.000018 in the European (non-Finnish) population of the Genome Aggregation Database though this is based on two alleles in a region of good sequence coverage so the variant is presumed to be rare. The evidence for this variant is limited. The p.Ala801Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Blueprint Genetics	RCV001073511	SCV001239056	likely pathogenic	Retinal dystrophy	2019-04-25	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV001353035	SCV001548150	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001683659	SCV001905574	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001683659	SCV002544294	likely pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Strong, PM1, PM2, PP4
Invitae	RCV001683659	SCV004292526	pathogenic	not provided	2023-09-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 631618). This missense change has been observed in individual(s) with clinical features of ABCA4-related conditions (PMID: 28559085, 32531858, 32619608; Invitae). This variant is present in population databases (rs374410829, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 801 of the ABCA4 protein (p.Ala801Thr).