Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000350.3(ABCA4):c.5584G>A (p.Gly1862Ser)

CA341280970

867094 (ClinVar)

Gene: ABCA4 (HGNC:24)

Condition: ABCA4-related retinopathy (MONDO:0800406)

Inheritance Mode: Autosomal recessive inheritance

UUID: 9f6b17c8-6b19-44f9-9a13-e1a6d26da6bd

Approved on: 2026-06-15

Published on: 2026-06-15

HGVS expressions

NM_000350.3:c.5584G>A

NM_000350.3(ABCA4):c.5584G>A (p.Gly1862Ser)

NC_000001.11:g.94011262C>T

CM000663.2:g.94011262C>T

NC_000001.10:g.94476818C>T

CM000663.1:g.94476818C>T

NC_000001.9:g.94249406C>T

NG_009073.1:g.114888G>A

ENST00000370225.4:c.5584G>A

ENST00000370225.3:c.5584G>A

ENST00000536513.5:c.1960G>A

NM_000350.2:c.5584G>A

Likely Pathogenic

PM3_Supporting PM2_Supporting PS1 PP3

PS4 PM5 PP4

Evidence Links 0

Expert Panel

ABCA4 VCEP

Criteria Specification Information

Criteria Specification: ClinGen ABCA4 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ABCA4 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ABCA4 VCEP

The NM_000350.3(ABCA4):c.5584G>A variant in ABCA4 is a missense variant predicted to cause substitution of glycine by serine at amino acid 1862 (p.Gly1862Ser). The total minor allele frequency in gnomAD v4.1.0 is 0.0000006196 (1/1614060 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The computational predictor REVEL gives a score of 0.661 which is in the range of 0.644-0.772, and SpliceAI gives a score of 0.69 which is above the threshold of >0.2, evidence that predicts a damaging effect on ABCA4 function (PP3). Another variant, c.5584G>C; p.Gly1862Arg, at the same nucleotide position has been classified as pathogenic by the ABCA4 VCEP. Splicing prediction using SpliceAI revealed similar predicted impacts on splicing for both variants (c.5584G>A donor loss score=0.69; c.5584G>C donor loss score=0.78) meeting PS1. At least one proband has been reported with a second pathogenic variant (c.6320G>A; p.Arg2107His) phase unknown meeting PM3_Supporting (0.5 points; LOVD database). In summary, this variant meets the criteria to be classified as likely pathogenic for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP specification version 1.0.0: PS1, PM3_Supporting, PM2_Supporting, PP3.

PM3_Supporting

At least one proband reported with a second pathogenic variant (c.6320G>A; p.Arg2107His) phase unknown. PM3 = 0.5.

PM2_Supporting

The total minor allele frequency in gnomAD v4.1.0 is 0.0000006196 (1/1614060 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001), meeting this criterion (PM2_Supporting).

PS1

Another variant, c.5584G>C (p.Gly1862Arg), at the same nucleotide position has been classified as pathogenic by the ABCA4 VCEP. Splicing prediction using SpliceAI revealed similar predicted impacts on splicing for both variants (c.5584G>A donor loss score=0.69; c.5584G>C donor loss score=0.78) (PS1).

PP3

The computational predictor REVEL gives a score of 0.661 which is in the range of 0.644-0.772, and SpliceAI gives a donor loss score of 0.69 which is above the threshold of >0.2, evidence that predicts a damaging effect on ABCA4 function (PP3).

PS4

The prevalence of the variant in affected individuals is not significantly increased compared with the prevalence in controls. The OR is infinity and the CI is 0.31-infinity, which is above the ABCA4 VCEP threshold of ≥5, however the CI does contain 1 (PMID: 35120629).

PM5

Another missense variant, c.5584G>C (p.Gly1862Arg), in the same codon has been classified as pathogenic by ClinVar, but Splice AI revealed expected effects on splicing (donor loss score=0.78). Since both variants have high SpliceAI scores, evaluating for PS1 given Walker et al. splicing guidance.

PP4

Four individuals from databases (ClinVar and LOVD) have been reported to have this variant, but none with a phenotypic description sufficient to meet PP4 criteria as specified by the ClinGen ABCA4 VCEP.

Curation History

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