rs606231422

Positions:

• chr2-203870684-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_005214.5(CTLA4):​c.208C>T​(p.Arg70Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CTLA4 NM_005214.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.34

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a mutagenesis_site Strongly reduced interaction with CD80, CD86 and ICOSLG. (size 0) in uniprot entity CTLA4_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 2-203870684-C-T is Pathogenic according to our data. Variant chr2-203870684-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTLA4	NM_005214.5	c.208C>T	p.Arg70Trp	missense_variant	2/4	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3	c.208C>T	p.Arg70Trp	missense_variant	2/3		NP_001032720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000648405.2	c.208C>T	p.Arg70Trp	missense_variant	2/4		NM_005214.5	ENSP00000497102.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 21, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 70 of the CTLA4 protein (p.Arg70Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features consistent with CTLA4-related conditions (PMID: 25329329, 30250467, 30940614, 33864888, 34128135; Invitae). ClinVar contains an entry for this variant (Variation ID: 161114). 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. Experimental studies have shown that this missense change affects CTLA4 function (PMID: 25329329). This variant disrupts the p.Arg70 amino acid residue in CTLA4. Other variant(s) that disrupt this residue have been observed in individuals with CTLA4-related conditions (PMID: 32499645), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 05, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 20, 2014	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 07, 2024	The c.208C>T (p.Arg70Trp) variant in the CTLA4 gene is likely pathogenic. The CTLA4 gene encodes a member of the immunoglobulin superfamily that transmits an inhibitory signal to T cells. Pathogenic variants in this gene are associated with autosomal dominant CTLA4 haploinsufficiency (ALPS-V), which is characterized by immune dysregulation with autoimmunity, immunodeficiency, and lymphoproliferation. This variant has been reported in the heterozygous state in patients with clinical features consistent with ALPS-V (PMIDs 37740092, 33864888, 34128135, 34824019) and has been reported to segregate with disease in two families (PMIDs 25329329, 38055819). This amino acid is highly conserved across species and there is a moderate physicochemical difference between arginine (Arg) and tryptophan (Trp). An in silico meta-predictor suggests that this amino acid change may impact protein function. In addition, two functional studies support that this variant results in reduced ligand binding ability of the encoded immunoglobulin (PMIDs 37740092, 25329329). Lastly, this variant is absent from large control databases (PMID 32461654). Criteria Applied: PS3_moderate, PS4_moderate, PM2_Supporting, PP1, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.036	D
MutationAssessor	Uncertain	2.7	M;M;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.8	.;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0010	.;D;D
Polyphen		1.0	D;D;.
Vest4		0.70, 0.69
MutPred		0.82		Loss of methylation at R70 (P = 0.0463);Loss of methylation at R70 (P = 0.0463);Loss of methylation at R70 (P = 0.0463);
MVP		0.89
MPC		1.7
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.84
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231422; hg19: chr2-204735407; COSMIC: COSV55592722;