Submissions for variant NM_000350.3(ABCA4):c.1411G>A (p.Glu471Lys)

gnomAD frequency: 0.00090  dbSNP: rs1800548

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000085395	SCV000336165	uncertain significance	not provided	2017-02-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085395	SCV000574772	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	ABCA4: BP4
Ambry Genetics	RCV000622340	SCV000742855	uncertain significance	Inborn genetic diseases	2017-08-28	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074274	SCV001239847	uncertain significance	Retinal dystrophy	2019-05-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001102041	SCV001258689	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	RCV000085395	SCV001725658	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000085395	SCV001802410	uncertain significance	not provided	2021-05-28	criteria provided, single submitter	clinical testing	Reported in individuals with Stargardt disease sometimes co-occurring with other ABCA4 variants, but it is not always known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Lewis et al., 1999; Rivera et al., 2000; Stone et al., 2003; Fujinami et al., 2013; Sharon et al., 2020); Published functional studies demonstrate no impact on ATP binding and hydrolysis (Sun et al., 2000); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31456290, 11017087, 23953153, 27535533, 9781034, 28446513, 12037008, 10090887, 16546111, 12796258, 27491360, 18977788, 19074458, 19230850, 25087612, 9295268, 9973280, 14971589, 10958763, 11919200)
Centogene AG - the Rare Disease Company	RCV001808322	SCV002059861	uncertain significance	Age related macular degeneration 2	2018-10-09	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003128228	SCV003804645	uncertain significance	Severe early-childhood-onset retinal dystrophy	2023-01-31	criteria provided, single submitter	clinical testing	This variant was identified together with NM_000350.3:c.1622T>C, NM_000350.3:c.3113C>T, NM_000350.3:c.2588G>C and NM_000350.3:c.5693G>A.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317086	SCV004020575	likely benign	not specified	2023-06-02	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.1411G>A (p.Glu471Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 251400 control chromosomes in GnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.00083 vs 0.0014), allowing no conclusion about variant significance. c.1411G>A has been reported in the literature in individuals affected with Retinitis Pigmentosa or Stargardt disease, but the second pathogenic variant and the phase information are not always known (example: Allikmets_1997, Lewis_1999, Hanany_2020, Reinhard_2007, Sharon_2019). These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variants have been reported (phase unknown with p.Gly863Ala and p.Asp1532Asn of ABCA4; in cis with c.4919G>A/p.Arg1640Gln of ABCA4), providing supporting evidence for a benign role (Fujinami_2013 and Mena_2021). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Sun_2000). The following publications have been ascertained in the context of this evaluation (PMID: 9295268, 23953153, 31964843, 33841504, 17562343, 10958763, 31456290, 11017087, 11328725). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS: 8, Likely pathognic: 1, Benign: 1) . Based on the evidence outlined above, the variant was classified as likely benign.
Retina International	RCV000085395	SCV000117532	not provided	not provided		no assertion provided	not provided
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002844	SCV001160866	likely pathogenic	Stargardt disease	2019-06-23	no assertion criteria provided	research