Submissions for variant NM_000350.3(ABCA4):c.1928T>G (p.Val643Gly)

gnomAD frequency: 0.00178  dbSNP: rs61754024

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408583	SCV000281837	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085446	SCV000321342	uncertain significance	not provided	2023-03-15	criteria provided, single submitter	clinical testing	Identified previously in other individual with features of an ABCA4-related disorder; however, the variant was either reported in the heterozygous state, or was seen with a second ABCA4 variant, phase unknown, whose pathogenicity was not established (Allikmets et al., 1997; Sciezynska et al., 2015; Rosenberg et al., 2007; Birtel et al., 2018; Sergouniotis et al., 2016); 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: 20981092, 27628848, 24265693, 17982420, 26593885, 29555955, 34426522, Scott2022[CaseReport], 34513887, 31429209, 32531858, 9295268)
CeGaT Center for Human Genetics Tuebingen	RCV000085446	SCV000608481	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	ABCA4: PM3, PM2:Supporting
Eurofins Ntd Llc (ga)	RCV000085446	SCV000700703	uncertain significance	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Invitae	RCV000085446	SCV001035550	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000085446	SCV001157612	uncertain significance	not provided	2023-10-09	criteria provided, single submitter	clinical testing	The ABCA4 c.1928T>G; p.Val643Gly variant (rs61754024) is reported in the medical literature in individuals with retinopathy in the heterozygous state without an additional pathogenic ABCA4 variant (Birtel 2018, Rosenberg 2007, Scienzynska 2016) and was originally described at a similar frequency in affected and unaffected individuals (Allikmets 1997). The variant is reported in the ClinVar database (Variation ID: 99102) and in the European (non-Finnish) population with an overall allele frequency of 0.3% (389/128892 alleles including 1 homozygote) in the Genome Aggregation Database. The valine at this position is highly conserve but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the variant is uncertain at this time. References: Allikmets R et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. 1997 Sep 19;277(5333):1805-7. Birtel J et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep. 2018 Mar 19;8(1):4824 Rosenberg T et al. N965S is a common ABCA4 variant in Stargardt-related retinopathies in the Danish population. Mol Vis. 2007 Oct 17;13:1962-9. Sciezynska A et al. Next-generation sequencing of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe. Exp Eye Res. 2016 Apr;145:93-99.
Blueprint Genetics	RCV001074170	SCV001239740	uncertain significance	Retinal dystrophy	2019-02-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001098278	SCV001254632	uncertain significance	ABCA4-Related Disorders	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085446	SCV001446941	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000408583	SCV001573568	uncertain significance	Severe early-childhood-onset retinal dystrophy	2021-04-08	criteria provided, single submitter	research	The ABCA4 c.1928T>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PP3. Based on this evidence we have classified this variant as Variant of Uncertain Significance.
Retina International	RCV000085446	SCV000117583	not provided	not provided		no assertion provided	not provided