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.203C>T (p.Pro68Leu)

CA226972

99113 (ClinVar)

Gene: ABCA4 (HGNC:24)

Condition: ABCA4-related retinopathy (MONDO:0800406)

Inheritance Mode: Autosomal recessive inheritance

UUID: 394c84d1-69af-4805-b847-44e46e199839

Approved on: 2025-12-05

Published on: 2025-12-22

HGVS expressions

NM_000350.3(ABCA4):c.203C>T (p.Pro68Leu)

NM_000350.3:c.203C>T

NC_000001.11:g.94111537G>A

CM000663.2:g.94111537G>A

NC_000001.10:g.94577093G>A

CM000663.1:g.94577093G>A

NC_000001.9:g.94349681G>A

NG_009073.1:g.14613C>T

ENST00000370225.4:c.203C>T

ENST00000649773.1:c.203C>T

ENST00000370225.3:c.203C>T

NM_000350.2:c.203C>T

Pathogenic

PM2_Supporting PP3_Moderate PS4 PP4 PM3

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.203C>T variant in ABCA4 is a missense variant predicted to cause substitution of proline by leucine at amino acid 68 (p.Pro68Leu). The total minor allele frequency in gnomAD v4.1.0 is 0.000005576 (9/1614086 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.954 which is above the threshold of >0.772, evidence that predicts a damaging effect on ABCA4 function (PP3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with an OR is 83.3 and the CI is 10.72-3671.60, which is above the ABCA4 VCEP threshold of ≥5, where the CI does not contain 1 (PS4; PMID: 35120629). At least one proband meet phenotypic criteria for an ABCA4-related retinopathy (PP4, PMID: 24713488). This variant has been detected in at least 3 individuals with ABCA4-related retinopathy with one of those individuals being a compound heterozygote for the variant and a pathogenic variant, c.5882 G>A; p.Gly1961Glu, which was confirmed in trans by parental testing (PM3; PMID: 26377081). In summary, this variant meets the criteria to be classified as pathogenic for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (Specification Version 1.0): PS4, PP4, PM3, PM2_Supporting, PP3_Moderate.

PM2_Supporting

The total minor allele frequency in gnomAD v4.1.0 is 0.000005576 (9/1614086 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001), meeting this criterion (PM2_Supporting).

PP3_Moderate

The computational predictor REVEL gives a score of 0.954 which is above the threshold of >0.772, evidence that predicts a damaging effect on ABCA4 function (PP3_Moderate).

PS4

The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. The OR is 83.3 and the CI is 10.72-3671.60, which is above the ABCA4 VCEP threshold of ≥5, where the CI does not contain 1 (PS4; PMID: 35120629).

PP4

At least one patient with this variant displayed presence of at least two ABCA4 variants, onset under 18 years of age, fundus autofluorescence, choriocapillaris dystrophy, and macular atrophy, which is highly specific for ABCA4-related retinopathy (PP4, PMID: 24713488).

PM3

This variant has been detected in at least 3 individuals with ABCA4-related retinopathy. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic variant, c.5882 G>A p.(Gly1961Glu), which was confirmed in trans by parental testing (PM3=1 point; PM3; PMID: 26377081).

Curation History

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