Submissions for variant NM_000350.3(ABCA4):c.618C>G (p.Ser206Arg)

dbSNP: rs61748536

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085793	SCV000321328	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing	Identified in individuals referred for genetic testing at GeneDx and in published literature with autosomal recessive ABCA4-related retinal dystrophies, including Stargardt disease and cone-rod dystrophy (Webster et al., 2001; Birch et al., 2001); Variant has also been observed in individuals with retinal dystrophy who had other disease-causing ABCA4 variants or variants in another gene that may have also contributed to the phenotype (Fishman et al., 1999; Eisenberger et al., 2013); Published functional studies demonstrate a damaging effect with reduced ATPase activity compared to wild type (Sun et al., 2000); This variant is associated with the following publications: (PMID: 22995991, 11017087, 24265693, 10206579, 17982420, 11328725, 11846518, 20647261, 32531858, 35456422, 36284670)
Eurofins Ntd Llc (ga)	RCV000391995	SCV000340118	benign	not specified	2016-04-19	criteria provided, single submitter	clinical testing
Invitae	RCV000085793	SCV001051202	benign	not provided	2024-01-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000986375	SCV001135365	uncertain significance	Severe early-childhood-onset retinal dystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV001074695	SCV001240288	uncertain significance	Retinal dystrophy	2020-06-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001098370	SCV001254730	uncertain significance	ABCA4-Related Disorders	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000391995	SCV003934467	uncertain significance	not specified	2023-05-12	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.618C>G (p.Ser206Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 280464 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency near the estimated frequency for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.0014 vs 0.0014). However, the variant is observed at a higher frequency in control chromosomes in the African population (10-fold above the estimated frequency for a pathogenic variant), providing conflicting evidence about variant significance. c.618C>G has been reported in the literature in individuals affected with Retinitis Pigmentosa, Stargardt disease, and other inherited retinal disorders (examples: Fishman_1999, Birch_2001, Webster_2001, Weisschuh_2020, Eisenberger_2013, Zhu_2022) both in the absence and presence of second variants with a range of pathogenicity, many with unknown pathogenicity. These data do not allow any conclusion about variant significance. In experimental studies, the variant was reported to have reduced basal ATPase activity and little stimulation by retinal (Sun_2000). The following publications have been ascertained in the context of this evaluation (PMID: 11846518, 10206579, 11328725, 32531858, 11017087, 24265693, 36284670). Six 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 (pathogenic (n=1), VUS (n=3), benign (n=2)). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003925093	SCV004756201	uncertain significance	ABCA4-related condition	2024-02-29	criteria provided, single submitter	clinical testing	The ABCA4 c.618C>G variant is predicted to result in the amino acid substitution p.Ser206Arg. This variant has been reported in patients with retinal disorders (Birch et al. 2001. PubMed ID: 11846518, Table 3; Webster et al. 2001. PubMed ID: 11328725, Table 1; Fishman et al. 1999. PubMed ID: 10206579, Table 1). Also, this variant was reported as an additional allele in a patient with autosomal recessive (AR) retinitis pigmentosa (RP) (Eisenberger et al. 2013. PubMed ID: 24265693, patient 89). Functional studies have shown that this variant reduces basal ATPase activity and shows little stimulation by retinal (Sun et al. 2000. PubMed ID: 11017087). The amino acid residue p.Ser206 of the ABCA4 protein has been highly conserved during evolution. This variant is reported in 1.5% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Retina International	RCV000085793	SCV000117936	not provided	not provided		no assertion provided	not provided