rs1553657378

Variant names:

• chr2-203870594-G-A
• rs1553657378
• NM_005214.5:c.118G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_005214.5(CTLA4):​c.118G>A​(p.Val40Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTLA4 NM_005214.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2
• Conservation: PhyloP100: 4.66
• Publications: 1 publications found

Genes affected

CTLA4 (HGNC:2505): (cytotoxic T-lymphocyte associated protein 4) This gene is a member of the immunoglobulin superfamily and encodes a protein which transmits an inhibitory signal to T cells. The protein contains a V domain, a transmembrane domain, and a cytoplasmic tail. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. Mutations in this gene have been associated with insulin-dependent diabetes mellitus, Graves disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases. [provided by RefSeq, Jul 2008]

CTLA4 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_005214.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 2-203870594-G-A is Pathogenic according to our data. Variant chr2-203870594-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 430906.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTLA4	NM_005214.5	c.118G>A	p.Val40Met	missense_variant	Exon 2 of 4	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3	c.118G>A	p.Val40Met	missense_variant	Exon 2 of 3		NP_001032720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000648405.2	c.118G>A	p.Val40Met	missense_variant	Exon 2 of 4		NM_005214.5	ENSP00000497102.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Apr 25, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PM2, PS4 -

May 08, 2018

Blueprint Genetics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

May 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency Pathogenic:2

Jun 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 40 of the CTLA4 protein (p.Val40Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CTLA4 haploinsufficiency (PMID: 28983403, 30048690, 34111452; Invitae). ClinVar contains an entry for this variant (Variation ID: 430906). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Val40 amino acid residue in CTLA4. Other variant(s) that disrupt this residue have been observed in individuals with CTLA4-related conditions (PMID: 29729943, 30048690, 34111452), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

-

Department of Immunology, University Hospital Southampton NHSFT

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Systemic lupus erythematosus;C0677607:Hashimoto thyroiditis;C1832392:Type 1 diabetes mellitus 12;C1857845:Celiac disease, susceptibility to, 3;C4015214:Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency Pathogenic:1

Jan 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Apr 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.118G>A (p.V40M) alteration is located in exon 2 (coding exon 2) of the CTLA4 gene. This alteration results from a G to A substitution at nucleotide position 118, causing the valine (V) at amino acid position 40 to be replaced by a methionine (M). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in individuals with features consistent with CTLA4-related immune dysregulation syndrome; in at least one individual, it was determined to be de novo (Rae, 2017; Rojas-Restrepo, 2021; Sogkas, 2022; Baxter, 2022; Erman, 2024). Another variant at the same codon, c.119T>C (p.V40A), has been identified in an individual with features consistent with CTLA4-related immune dysregulation syndrome (Miyazaki, 2022). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.6	M;M;M;M
PhyloP100		4.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	.;N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Uncertain	0.011	.;D;D;T
Polyphen		1.0	D;D;.;D
Vest4		0.52, 0.51, 0.69
MutPred		0.83		Gain of ubiquitination at K36 (P = 0.1306);Gain of ubiquitination at K36 (P = 0.1306);Gain of ubiquitination at K36 (P = 0.1306);Gain of ubiquitination at K36 (P = 0.1306);
MVP		0.67
MPC		1.3
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.56
gMVP		0.65
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1553657378; hg19: chr2-204735317;