Submissions for variant NM_000350.3(ABCA4):c.1140T>A (p.Asn380Lys)

gnomAD frequency: 0.00066  dbSNP: rs61748549

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085376	SCV000321335	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Identified in patients with Stargardt disease and retinitis pigmentosa in published literature, however a second ABCA4 variant was not identified in these cases (Webster et al., 2001; Valverde et al., 2006; Valverde et al., 2007; Smaragda et al., 2018); Identified in a patient with retinitis pigmentosa in published literature who also had two loss-of-function variants in the CEP290 gene (Eisenberger et al., 2013); 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: 18977788, 16917483, 17325136, 14709597, 34426522, 32641690, 29854428, 26355662, 11328725, 35836572, 32000842, 24265693)
Eurofins Ntd Llc (ga)	RCV000085376	SCV000702698	uncertain significance	not provided	2016-11-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764205	SCV000895208	uncertain significance	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
Mendelics	RCV000986372	SCV001135362	uncertain significance	Severe early-childhood-onset retinal dystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001073759	SCV001239319	uncertain significance	Retinal dystrophy	2017-11-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085376	SCV001247756	uncertain significance	not provided	2020-01-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001096640	SCV001252865	uncertain significance	ABCA4-related disorder	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085376	SCV001414645	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Retina International	RCV000085376	SCV000117513	not provided	not provided		no assertion provided	not provided
Faculty of Health Sciences, Beirut Arab University	RCV001257823	SCV001434607	pathogenic	Autosomal recessive retinitis pigmentosa	2015-09-10	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV001096640	SCV004740230	uncertain significance	ABCA4-related disorder	2024-01-27	no assertion criteria provided	clinical testing	The ABCA4 c.1140T>A variant is predicted to result in the amino acid substitution p.Asn380Lys. This variant has been reported in multiple individuals with autosomal recessive retinal dystrophies (see for example, Table S1, Patel et al. 2015. PubMed ID: 26355662; Table 1, Riveiro-Alvarez et al 2013. PubMed ID: 23755871; Table S4, Maltese et al. 2022. PubMed ID: 35836572). However, in Riveiro-Alvarez et al. this variant was reported in cis with another variant as c.[1140T>A; 5395A>G] (p.[Asn380Lys; Asn1799Asp]). This variant is reported in 0.091% of alleles in individuals of European (non-Finnish) descent in gnomAD, indicating it is relatively common. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.