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_005214.5(CTLA4):c.105C>A (p.Cys35Ter)

CA173996

161112 (ClinVar)

Gene: CTLA4 (HGNC:1493)

Condition: autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency (MONDO:0014493)

Inheritance Mode: Autosomal dominant inheritance

UUID: 8e9de9f6-62fc-4c73-b8f4-064921299471

Approved on: 2025-11-24

Published on: 2025-12-02

HGVS expressions

NM_005214.5:c.105C>A

NM_005214.5(CTLA4):c.105C>A (p.Cys35Ter)

NC_000002.12:g.203868047C>A

CM000664.2:g.203868047C>A

NC_000002.11:g.204732770C>A

CM000664.1:g.204732770C>A

NC_000002.10:g.204441015C>A

NG_011502.1:g.5262C>A

ENST00000696049.1:c.105C>A

ENST00000696479.1:c.177C>A

ENST00000648405.2:c.105C>A

ENST00000295854.10:c.105C>A

ENST00000302823.7:c.105C>A

ENST00000472206.1:c.105C>A

ENST00000487393.1:n.105C>A

NM_001037631.2:c.105C>A

NM_005214.4:c.105C>A

NM_001037631.3:c.105C>A

Pathogenic

PP1_Strong PVS1 PP4

PM2 BA1 BS4 BS1 PS4 PS3

Evidence Links 0

Expert Panel

Antibody Deficiencies VCEP

Criteria Specification Information

Criteria Specification: ClinGen Antibody Deficiencies Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CTLA4 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Antibody Deficiencies VCEP

NM_005214.5(CTLA4):c.105C>A (p.Cys35Ter) is a nonsense variant that introduces a premature stop codon into exon 1 of 4 and is predicted to trigger nonsense-mediated decay in CTLA4, in which loss-of-function is an established mechanism of disease (PVS1). Chinese hamster ovary cells overexpressing the variant showed abolished uptake of labeled CD80-Ig ligand relative to the wild-type CTLA4 control, indicating that this variant disrupts protein function (PMID: 25329329). However, PVS1 has already been met, so the PS3_Supporting code is not counted. This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000001242, with 2 alleles / 1,609,900 total alleles across all populations of gnomAD, which is higher than the ClinGen Antibody Deficiencies VCEP PM2_Supporting threshold of <0.000000143. This variant has a GrpMax allele frequency of 0.00000028, with 2 alleles / 1,176,158 total alleles in the European (non-Finnish) population, which is lower than the BS1 threshold of >0.00000111, so no population code is met. At least one patient harboring this variant has a phenotype that includes diarrhea / enteropathy (4 pts), hypogammaglobulinemia (2 pts), respiratory tract infections (4 pts), splenomegaly (2 pts), autoimmune thyroiditis (1 pt), and autoimmune arthritis (1 pt), with genotyping by exome sequencing identifying no alternative basis for disease in other loci, which together are specific for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (14 total points, PMID: 25329329, PP4). The variant has been reported to segregate with autoimmune and lymphoproliferative syndrome due to CTLA4 haploinsufficiency through 5 affected meioses from 1 family (PMID: 25329329, PP1_Strong). Affected status has been confirmed for all 4 family members (at least 6 phenotype points). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Antibody Deficiencies VCEP: PVS1, PP4, and PP1_Strong. (VCEP specifications version 1.0.0; date of approval 09/18/2025).

PP1_Strong

The variant has been reported to segregate with autoimmune and lymphoproliferative syndrome due to CTLA4 haploinsufficiency through 5 affected meioses from 1 family (PMID: 25329329, PP1_Strong). All 4 affected family members are confirmed to be severely affected (at least 6 phenotype points).

PVS1

PP4

At least one patient harboring this variant has a phenotype that includes diarrhea / enteropathy (4 pts), hypogammaglobulinemia (2 pts), respiratory tract infections (4 pts), splenomegaly (2 pts), autoimmune thyroiditis (1 pt), and autoimmune arthritis (1 pt), with genotyping by exome sequencing identifying no alternative basis for disease in other loci, which together are specific for autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (14 total points, PMID: 25329329, PP4).

PM2

This variant is present in gnomAD v4.1.0 at a total allele frequency of 0.000001242, with 2 alleles / 1,609,900 total alleles across all populations of gnomAD, which is higher than the ClinGen Antibody Deficiencies VCEP PM2_Supporting threshold of <0.000000143.

BA1

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

BS4

All family members affected carry the variant p.Cys50Ter. By contrast, some family members considered healthy were found to be carriers of the variants. Subsequent clinical follow-up indicated that some carriers showed mild or incomplete phenotypes compare to affected individuals.

BS1

This variant is present in gnomAD v4.1.0 at a GrpMax allele frequency of 0.00000028, with 2 alleles / 1,176,158 total alleles in the European (non-Finnish) population, which is lower than the BS1 threshold of >0.00000111.

PS4

This variant has been reported in 1 proband meeting the ClinGen Antibody Deficiencies VCEP standard for phenotypic criteria. The proband exceeded 10 phenotypic points without genotyping that excluded causes in other loci, which together are highly consistent with CTLA4 insufficiency (PMID: 25329329). The proband was already counted for PP4, so PS4_Supporting was not met.

PS3

Transendocytosis assay in Chinese hamster ovary cells overexpressing the variant showed completely abolished CD80-Ig ligand transendocytosis relative to the wild-type control, indicating that this variant disrupts protein function (PMID: 25329329). PVS1 has already been met, so the PS3_Supporting code was not counted.

Curation History

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