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:c.4793C>A

CA227239

99321 (ClinVar)

Gene: ABCA4 (HGNC:24)

Condition: ABCA4-related retinopathy (MONDO:0800406)

Inheritance Mode: Autosomal recessive inheritance

UUID: 399dfd75-c421-4659-9305-1b953c22709b

Approved on: 2026-08-25

Published on: 2026-08-25

HGVS expressions

NM_000350.3:c.4793C>A

NC_000001.11:g.94021695G>T

CM000663.2:g.94021695G>T

NC_000001.10:g.94487251G>T

CM000663.1:g.94487251G>T

NC_000001.9:g.94259839G>T

NG_009073.1:g.104455C>A

ENST00000370225.4:c.4793C>A

ENST00000370225.3:c.4793C>A

ENST00000460514.1:n.287C>A

ENST00000536513.5:c.1169C>A

NM_000350.2:c.4793C>A

Pathogenic

PM3_Strong PS3_Supporting PS4 PM2_Supporting PP4 PP3

Evidence Links 1

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ABCA4 VCEP

The NM_000350.3:c.4793C>A variant is a missense variant predicted to cause this substitution of alanine to aspartic acid at amino acid 1598 (p.Ala1598Asp). The total minor allele frequency in gnomAD v4.1.1 is 0.00002046 (<0.0001) which is lower than the threshold for PM2_Supporting. The computational predictor REVEL gives a score of 0.685 which is in the range of 0.644-0.772, evidence that predicts a damaging effect on ABCA4 function (PP3). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with an OR of 187.4 and CI of 60.33 to 933.94, which is above the ABCA4 VCEP threshold of ≥5 where the CI does not contain 1 (PS4; PMID: 35120629). This variant has been detected in at least three individuals with ABCA4-related retinopathy. At least one patient with this variant displayed presence of at least two ABCA4 variants, onset under 18 years of age, reduced central vision bilaterally and on the presence of “dark choroid” sign of fluorescein angiography, and scotomas, which is highly specific for ABCA4-related retinopathy (PP4, PMID: 27014590). Two were compound heterozygous for the variant and a pathogenic variant and one of those was confirmed in trans by parental testing, and one individual was homozygous for the variant (PM3_Strong; PMIDs: 27014590, 34874912, 41677386). ABCA4 expression and ATPase activity in HEK293 cells showed significant reduction of more than 20% compared to wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 32845050). In summary, this variant meets the criteria to be classified as pathogenic for ABCA4-related retinopathy, specifically when co-occurring with other disease-causing ABCA4 variants, based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0): PS4, PM3_Strong, PP4, PP3, PS3_Supporting, PM2_Supporting.

PM3_Strong

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS3_Supporting

ABCA4 expression and ATPase activity in HEK293 cells showed significant reduction of more than 20% compared to wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 32845050).

Transfected HEK293T cells with variant showed Relative Expression 0.64±0.19. Relative ATPase Activity ATPase–ATR 0.48±0.21. Relative ATPase Activity ATPase+ATR 0.32±0.12 compared to wildtype. (Table 1) PubMed:32845050

PS4

The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. The OR is 187.4 and the CI is 60.33 to 933.94, which is above the ABCA4 VCEP threshold of ≥5, where the CI does not contain 1 (PS4; PMID: 35120629).

PM2_Supporting

The total minor allele frequency in gnomAD v4.1.1 is 0.00002046 (33/1613150 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001), meeting this criterion (PM2_Supporting).

PP4

At least one patient with this variant displayed presence of at least two ABCA4 variants, onset under 18 years of age, reduced central vision bilaterally and on the presence of “dark choroid” sign of fluorescein angiography, and scotomas, which is highly specific for ABCA4-related retinopathy (PP4, PMID: 27014590).

PP3

The computational predictor REVEL gives a score of 0.685 which is in the range of 0.644-0.772, evidence that predicts a damaging effect on ABCA4 function (PP3).

Curation History

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