Submissions for variant NM_000350.3(ABCA4):c.2791G>A (p.Val931Met)

gnomAD frequency: 0.00136  dbSNP: rs58331765

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000085506	SCV000701679	likely pathogenic	not provided	2016-10-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085506	SCV001102458	pathogenic	not provided	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 931 of the ABCA4 protein (p.Val931Met). This variant is present in population databases (rs58331765, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Stargardt disease (PMID: 9054934, 9973280, 19365591, 23755871, 28430335, 29114839, 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: 7880). 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	RCV001073603	SCV001239154	pathogenic	Retinal dystrophy	2019-07-12	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV001807722	SCV002058458	pathogenic	Retinitis pigmentosa 19	2022-01-03	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: VCV000007880, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000865894, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.664, PP3_P). A missense variant is a common mechanism associated with Retinitis pigmentosa 19 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000474, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV000085506	SCV002098161	likely pathogenic	not provided	2024-10-16	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22264887, 27884173, 19365591, 9973280, 31456290, 9054934, 23755871, 30093795, 32619608, 24123366, 18977788, 35119454, 31816670, 27535533, 37498587, 35120629, 31964843, 32307445, 36011402)
Mendelics	RCV002247267	SCV002516813	pathogenic	not specified	2022-08-08	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000008330	SCV002557573	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cone-rod dystrophy 3 (MIM#604116), fundus flavimaculatus (MIM#248200), early-onset severe retinal dystrophy (MIM#248200), retinitis pigmentosa 19 (MIM#601718) and Stargardt disease 1 (MIM#248200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 190 heterozygotes, 0 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (p.(Val931Ala)) (7 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ABC transporter domain 1 (UniProt). (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. The p.(Val931Leu) variant has been classified as both Pathogenic and Variant of Uncertain Significance, with limited or no evidence for their respective classification (ClinVar; PMID: 31213501). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in multiple individuals with Stargardt disease; however it should be noted that some studies have also classified this variant as benign or likely benign (ClinVar; PMIDs: 9054934, 23755871, 23755871, 30093795, 23769331, 25082829, 31456290, 32619608). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000350.2(ABCA4):c.4981del; p.(Leu1661*)) in a recessive disease. Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000085506	SCV004847386	uncertain significance	not provided	2023-12-18	criteria provided, single submitter	clinical testing	The p.Val931Met variant in ABCA4 has been reported in the homozygous and compound heterozygous state in >10 individuals with Stargardt disease, however it was also found with other variants in ABCA4 in some affected individuals that could potentially explain their disease. This variant segregated with disease in 1 affected homozygous relative from a consanguineous family (Allikmets 1997 PMID: 9054934, Lewis 1999 PMID: 9973280, Maia-Lopes 2009 PMID: 19365591, Fujinami 2013 PMID: 23769331, Riveiro-Alvarez 2013 PMID: 23755871, Vallim-Salles 2017 PMID: 29114839, Pozo-Valero 2020 PMID: 32619608). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 7880). It has also been identified in 0.4% (177/41416) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_Strong.
Fulgent Genetics, Fulgent Genetics	RCV005025030	SCV005659514	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-06-07	criteria provided, single submitter	clinical testing
OMIM	RCV000008330	SCV000028538	pathogenic	Severe early-childhood-onset retinal dystrophy	1997-03-01	no assertion criteria provided	literature only
Retina International	RCV000085506	SCV000117643	not provided	not provided		no assertion provided	not provided
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002838	SCV001160858	pathogenic	Stargardt disease	2019-06-23	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004732538	SCV005351958	likely pathogenic	ABCA4-related disorder	2024-04-09	no assertion criteria provided	clinical testing	The ABCA4 c.2791G>A variant is predicted to result in the amino acid substitution p.Val931Met. This variant has been reported in the compound heterozygous state many times in individuals with retinal dystrophy (see for examples Allikmets et al. 1997. PubMed ID: 9054934; Salles et al. 2018. PubMed ID: 30093795; Del Pozo-Valero et al. 2020. PubMed ID: 32619608; Table S2 in Sharon et al. 2020. PubMed ID: 31456290). This variant is reported in 0.44% of alleles in individuals of African descent in gnomAD, indicating it is relatively common. This variant has been listed as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/7880/). Given the evidence, we interpret this variant as likely pathogenic.