Submissions for variant NM_000350.3(ABCA4):c.514G>A (p.Gly172Ser)

gnomAD frequency: 0.00033  dbSNP: rs61748532

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001073775	SCV001239336	likely pathogenic	Retinal dystrophy	2018-01-11	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196794	SCV001367427	uncertain significance	Age related macular degeneration 2	2019-11-12	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PP2,PP3.
Invitae	RCV000085700	SCV001421148	pathogenic	not provided	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 172 of the ABCA4 protein (p.Gly172Ser). This variant is present in population databases (rs61748532, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of ABCA4-related conditions (PMID: 19265867, 25922843; Invitae). 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: 99347). 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 not expected to disrupt ABCA4 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Molecular Genetics, University of Zurich	RCV001353027	SCV001548138	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449733	SCV001653004	likely pathogenic	Stargardt disease	2020-06-19	criteria provided, single submitter	clinical testing	The p.Gly172Ser variant in ABCA4 has been reported previously in 1 individual (zygosity not indicated) and in 3 compound heterozygous individuals with Stargardt disease (one had a second variant c.570+1G>A; the other individual carried 2 additional missense variants in cis (p.Val675Ile (ClinVar ID 288341) and p.Val2050Leu (ClinVar ID 7884), and a frameshift variant in trans (p.Ser1071fsX14); and the third individual carried p.Gly1961Glu (ClinVar ID 7888) in trans) (Jaakson 2003 PMID:14517951, Battu 2015 PMID: 25922843, Riera 2019 PMID: 30798147, Verdina 2017 PMID: 28365912). It has also been reported in ClinVar (Variation ID 99347) and identified in 0.07% (24/35440) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Stargardt disease. ACMG/AMP Criteria applied: PP3, PM3_Strong, PM2_Supporting.
CeGaT Center for Human Genetics Tuebingen	RCV000085700	SCV004124082	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing
Retina International	RCV000085700	SCV000117840	not provided	not provided		no assertion provided	not provided
Clinical Genetics, Academic Medical Center	RCV000085700	SCV001917404	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085700	SCV001954622	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000085700	SCV001969644	uncertain significance	not provided		no assertion criteria provided	clinical testing