Submissions for variant NM_000350.3(ABCA4):c.1253T>C (p.Phe418Ser)

gnomAD frequency: 0.00001  dbSNP: rs794726979

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000173679	SCV000321336	pathogenic	not provided	2021-01-18	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported as pathogenic in ClinVar but additional evidence is not available (ClinVar Variation ID 193580; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 28559085, 26720470, 21911583, 23499370, 30055151, 23143460, 28771251, 29555955, 28341476, 30834176)
Eurofins Ntd Llc (ga)	RCV000173679	SCV000331703	pathogenic	not provided	2016-08-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000173679	SCV001205468	pathogenic	not provided	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 418 of the ABCA4 protein (p.Phe418Ser). This variant is present in population databases (rs794726979, gnomAD 0.002%). This missense change has been observed in individual(s) with ABCA4-related conditions (PMID: 21911583, 28341476, 28559085, 29555955, 30834176). 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: 193580). 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	RCV001073557	SCV001239106	pathogenic	Retinal dystrophy	2019-06-15	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000173679	SCV001447928	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001073557	SCV005068586	likely pathogenic	Retinal dystrophy	2021-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237645	SCV005887316	pathogenic	Retinitis pigmentosa	2025-01-14	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.1253T>C (p.Phe418Ser) 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 1.2e-05 in 251470 control chromosomes (gnomAD). c.1253T>C has been reported in the literature in multiple individuals affected with ABCA4-related conditions (examples : Zernant_2011, Stone_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21911583, 28559085, 29555955, 37734845, 38219857, 28771251). ClinVar contains an entry for this variant (Variation ID: 193580). Based on the evidence outlined above, the variant was classified as pathogenic.