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.6445C>T (p.Arg2149Ter)

CA227404

99460 (ClinVar)

Gene: ABCA4 (HGNC:24)

Condition: ABCA4-related retinopathy (MONDO:0800406)

Inheritance Mode: Autosomal recessive inheritance

UUID: 2a28d610-baee-43f6-9eef-6d2f37a33593

Approved on: 2025-12-05

Published on: 2025-12-23

HGVS expressions

NM_000350.3:c.6445C>T

NM_000350.3(ABCA4):c.6445C>T (p.Arg2149Ter)

NC_000001.11:g.94000870G>A

CM000663.2:g.94000870G>A

NC_000001.10:g.94466426G>A

CM000663.1:g.94466426G>A

NC_000001.9:g.94239014G>A

NG_009073.1:g.125280C>T

ENST00000370225.4:c.6445C>T

ENST00000370225.3:c.6445C>T

ENST00000536513.5:c.2821C>T

NM_000350.2:c.6445C>T

Pathogenic

PM3_Supporting PVS1 PM2_Supporting PS4

BS1

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:c.6445C>T (p.Arg2149Ter) variant in ABCA4 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 47 out of 50 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The total minor allele frequency in gnomAD v4.1.0 is 0.000006196 (10/1614050 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with and OR of 86.3 and the CI is 30.40-338.60, 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 1 individual who was homozygous for the variant (PMID: 36284460; PM3_Supporting). 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: PVS1, PS4, PM3_Supporting, PM2_Supporting.

PM3_Supporting

This variant has been detected in at least 1 individual with ABCA4-related retinopathy. This individual was homozygous for the variant (PM3= 0.5points, PMID: 36284460; PM3_Supporting).

PVS1

This is a nonsense variant located in exon 47 out of 50, and introduces a premature stop codon between codons 1-2255 (PVS1).

PM2_Supporting

The total minor allele frequency in gnomAD v4.1.0 is 0.000006196 (10/1614050 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001), meeting this criterion (PM2_Supporting).

PS4

The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. The OR is 86.3 and the CI is 30.40-338.60, which is above the ABCA4 VCEP threshold of >3, where the CI does not contain 1 (PS4; PMID: 35120629).

BS1

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

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.