Submissions for variant NM_000350.3(ABCA4):c.634C>T (p.Arg212Cys)

gnomAD frequency: 0.00008  dbSNP: rs61750200

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000085812	SCV000231518	pathogenic	not provided	2016-11-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000085812	SCV000321329	pathogenic	not provided	2022-04-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with reduced protein expression and reduced ATP binding capacity (Sun et al., 2000; Curtis et al., 2020); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10958761, 18977788, 22264887, 26909568, 25082829, 23891399, 28559085, 9503029, 9781034, 10711710, 11385708, 27014590, 27820952, 26161775, 15108289, 11726554, 19028736, 25082885, 25283059, 16546111, 29555955, 28224992, 25741868, 30093795, 10958763, 29925512, 32141364, 31766579, 30820146, 33851411, 31589614, 32619608, 34327195, 34426522, 32845068, 31456290, 32845050, 32467599, 32036094, 32581362, 11017087)
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000179293	SCV000891271	likely pathogenic	Cone-rod dystrophy 3	2017-09-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763050	SCV000893531	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085812	SCV001203674	pathogenic	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 212 of the ABCA4 protein (p.Arg212Cys). This variant is present in population databases (rs61750200, gnomAD 0.05%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 10458172, 10711710, 26161775, 29925512, 30093795). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7898). 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	RCV001074780	SCV001240376	pathogenic	Retinal dystrophy	2019-06-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085812	SCV001247759	pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085812	SCV001447681	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV000008355	SCV001548033	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000008355	SCV002318863	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-03-22	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007898, PMID:9503029). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 29925512, 30093795, 26161775) and it has been co-segregated with Stargardt disease 1 in multiple affected family members (PMID: 10711710). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.847>=0.6, 3CNET: 0.973>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0001195). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
AiLife Diagnostics, AiLife Diagnostics	RCV000085812	SCV002503431	pathogenic	not provided	2020-05-11	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000008355	SCV004175841	pathogenic	Severe early-childhood-onset retinal dystrophy	2023-02-14	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074780	SCV005069622	pathogenic	Retinal dystrophy	2022-01-01	criteria provided, single submitter	clinical testing
OMIM	RCV000008355	SCV000028563	pathogenic	Severe early-childhood-onset retinal dystrophy	2001-06-01	no assertion criteria provided	literature only
Retina International	RCV000085812	SCV000117955	not provided	not provided		no assertion provided	not provided
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000008355	SCV000804586	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-09-01	no assertion criteria provided	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787521	SCV000926489	pathogenic	Stargardt disease	2018-04-01	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000787521	SCV001160869	pathogenic	Stargardt disease	2019-06-23	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000085812	SCV001918385	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085812	SCV001951631	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV004558240	SCV005046929	pathogenic	Stargardt disease 3		no assertion criteria provided	research