Submissions for variant NM_000350.3(ABCA4):c.1343T>A (p.Met448Lys)

dbSNP: rs777078540

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000388365	SCV001583711	pathogenic	not provided	2024-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 448 of the ABCA4 protein (p.Met448Lys). This variant is present in population databases (rs777078540, gnomAD 0.02%). This missense change has been observed in individuals with Stargardt disease (PMID: 26593885, 29847635). ClinVar contains an entry for this variant (Variation ID: 288325). 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%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 29847635). This variant disrupts the p.Met448 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26593885, 29847635). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816512	SCV005069965	pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586668	SCV005077368	likely pathogenic	Stargardt disease	2024-04-05	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.1343T>A (p.Met448Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251430 control chromosomes. c.1343T>A has been reported in the literature in individuals affected with Stargardt Disease. These data indicate that the variant may be associated with disease( Garces_2018, Sciezynska_2016). At least one publication reports experimental evidence evaluating an impact on protein function shows a severe impact on substrate binding and basal activity (Garces_2018). The following publications have been ascertained in the context of this evaluation (PMID: 26593885, 29847635). ClinVar contains an entry for this variant (Variation ID: 288325). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV000388365	SCV005437475	pathogenic	not provided	2024-06-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a significant effect on substrate binding and ATPase activity in vitro (PMID: 29847635); 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: 35120629, 29847635, 26593885)
Fulgent Genetics, Fulgent Genetics	RCV005025431	SCV005663579	likely pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-04-10	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000388365	SCV000342405	uncertain significance	not provided	2016-06-27	flagged submission	clinical testing