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.4195G>T (p.Glu1399Ter)

CA957690

236109 (ClinVar)

Gene: ABCA4 (HGNC:24)

Condition: ABCA4-related retinopathy (MONDO:0800406)

Inheritance Mode: Autosomal recessive inheritance

UUID: fe461120-c272-4629-8a0b-12434a710c24

Approved on: 2025-12-16

Published on: 2025-12-19

HGVS expressions

NM_000350.3(ABCA4):c.4195G>T (p.Glu1399Ter)

NM_000350.3:c.4195G>T

NC_000001.11:g.94031054C>A

CM000663.2:g.94031054C>A

NC_000001.10:g.94496610C>A

CM000663.1:g.94496610C>A

NC_000001.9:g.94269198C>A

NG_009073.1:g.95096G>T

ENST00000370225.4:c.4195G>T

ENST00000370225.3:c.4195G>T

ENST00000536513.5:c.571G>T

NM_000350.2:c.4195G>T

Pathogenic

PP1_Moderate PP4 PVS1 PM2_Supporting

PS4

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.4195G>T (p.Glu1399Ter) variant in ABCA4 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 28/50 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 0.0000018 (3/1613986 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). At least one proband was reported meeting criteria for ABCA4-related retinopathy (PP4, PMID:26161775). The variant has been reported to segregate with ABCA4-related retinopathy in the proband and 2 similarly affected relatives (PP1_Moderate; PMID:26161775). 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 1.0.0): PVS1, PP4, PP1_Moderate, PM2_Supporting.

PP1_Moderate

The variant has been reported to segregate with ABCA4-related retinopathy in the proband and 2 similarly affected relatives (PP1_Moderate; PMID:26161775).

PP4

At least one patient with this variant displayed presence of at least two ABCA4 variants, onset under 18 years of age, beaten-bronze appearance and pigment disorder on fundus, and decreased central visual acutity. This patient also underwent exome sequencing. This phenotype is highly specific for ABCA4-related retinopathy (PP4, PMID:26161775).

PVS1

This is a nonsense variant located in exon 28 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 0.0000018 (3/1613986 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001), meeting this criterion (PM2_Supporting).

PS4

OR = 6.0, CI is 0.10 - 114.44

Curation History

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