Submissions for variant NM_000350.3(ABCA4):c.5881G>A (p.Gly1961Arg)

gnomAD frequency: 0.00007  dbSNP: rs142253670

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408510	SCV000281938	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778996	SCV000915437	likely pathogenic	ABCA4-Related Disorders	2018-10-24	criteria provided, single submitter	clinical testing	The ABCA4 c.5881G>A (p.Gly1961Arg) missense variant has been reported in three studies in which it is found in a total of three individuals with Stargardt disease in a compound heterozygous state, in two with a frameshift variant on the second allele and in one with a missense variant on the second allele (Cideciyan et al. 2009; Riveiro-Alvarez et al. 2013; Jiang et al. 2016). The variant has not been reported in the literature in any other conditions potentially associated with variants in the ABCA4 gene. The p.Gly1961Arg variant was absent from 100 control individuals, but is reported at a frequency of 0.00024 in the South Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Gly1961Arg variant is classified as likely pathogenic for Stargardt disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001229952	SCV001402415	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1961 of the ABCA4 protein (p.Gly1961Arg). This variant is present in population databases (rs142253670, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive Stargardt disease (PMID: 19074458, 23755871, 26780318, 28118664). 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: 236140). 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 expected to disrupt ABCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly1961 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19074458, 28181551, 28559085, 30060493). 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.
GeneDx	RCV001229952	SCV001780768	likely pathogenic	not provided	2020-10-20	criteria provided, single submitter	clinical testing	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: 25525159, 23755871, 32090030, 33090715, 26780318, 31589614, 28118664, 19074458)