Submissions for variant NM_000350.3(ABCA4):c.2819C>G (p.Pro940Arg)

gnomAD frequency: 0.00034  dbSNP: rs144995371

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000316390	SCV000340406	uncertain significance	not provided	2016-03-17	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001075267	SCV001240882	uncertain significance	Retinal dystrophy	2017-09-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001101951	SCV001258595	uncertain significance	ABCA4-related disorder	2018-01-30	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000316390	SCV001420818	uncertain significance	not provided	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 940 of the ABCA4 protein (p.Pro940Arg). This variant is present in population databases (rs144995371, gnomAD 0.06%). This missense change has been observed in individual(s) with ABCA4-related conditions, macular degeneration, and/or Stargardt disease (PMID: 10634626, 18024811, 30060493, 33258285; internal data). ClinVar contains an entry for this variant (Variation ID: 286835). 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 not expected to disrupt ABCA4 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11919200, 23144455). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV002487242	SCV002777616	uncertain significance	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2021-09-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075267	SCV005072934	uncertain significance	Retinal dystrophy	2013-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786655	SCV005399260	uncertain significance	Cone-rod dystrophy 3	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine (exon 19). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 (80 Heterozygous, 0 Homozygous). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 Heterozygous, 0 Homozygous). (N) 0502 - Missense variant with conflicting in silico predictions and low conservation. (N) 0600 - Variant is located in an annotated domain or motif (NBD1 domain; PMID: 11919200). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are inconclusive (ClinVar; PMID: 21911583; PMID: 18024811; PMID: 30060493). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1002 - Moderate functional evidence supporting abnormal protein function (PMID: 23144455). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Clinical Genetics, Academic Medical Center	RCV000316390	SCV001919060	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000316390	SCV001971322	uncertain significance	not provided		no assertion criteria provided	clinical testing