rs606231422

Variant names:

• chr2-203870684-C-T
• rs606231422
• NM_005214.5:c.208C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70Q) has been classified 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:6
• Conservation: PhyloP100: 1.34
• Publications: 16 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: Pathogenic. The variant received 18 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, 11 uncertain in NM_005214.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-203870685-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 811325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 161114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTLA4	NM_005214.5	c.208C>T	p.Arg70Trp	missense_variant	Exon 2 of 4	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3	c.208C>T	p.Arg70Trp	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.208C>T	p.Arg70Trp	missense_variant	Exon 2 of 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Nov 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on protein function (PMID: 25329329, 37740092); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 34128135, 34824019, 33864888, 37740092, 35999394, 30940614, 34111452, 38055819, 37161048, 8792965, 36443461, 36008610, 25329329, 29729943) -

Oct 07, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency Pathogenic:3

Aug 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 20, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 05, 2020

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

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
PhyloP100		1.3
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

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