rs606231417

Positions:

• chr2-203870627-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005214.5(CTLA4):​c.151C>T​(p.Arg51*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTLA4 NM_005214.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.30

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-203870627-C-T is Pathogenic according to our data. Variant chr2-203870627-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 161109.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.151C>T	p.Arg51*	stop_gained	2/4	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3	c.151C>T	p.Arg51*	stop_gained	2/3		NP_001032720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000648405.2	c.151C>T	p.Arg51*	stop_gained	2/4		NM_005214.5	ENSP00000497102.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

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	Dec 10, 2023	This sequence change creates a premature translational stop signal (p.Arg51*) in the CTLA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTLA4 are known to be pathogenic (PMID: 25213377, 25329329). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with CTLA4 deficiency (PMID: 25213377). ClinVar contains an entry for this variant (Variation ID: 161109). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 26, 2014	- -
Likely pathogenic, no assertion criteria provided	research	National Institute of Immunohaematology, Indian Council of Medical Research	-	The variant Arg51Ter has been associated with CTLA4 haploinsufficiency , as reported in a previous study (PMID: 32499327). The variant is not identified in any public databases and the sequence is conserved . the insilco prediction analysis of the variant is damaging by SIFT, polyphen and mutation taster. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2023	PM2, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 17, 2018	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 12, 2024

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2020

The alteration results in a premature stop codon: _x000D_ _x000D_ The c.151C>T (p.R51*) alteration, located in coding exon 2 of the CTLA4 gene, results from a C to T substitution at nucleotide position 151. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 51. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration has been reported in multiple patients with immune related symptoms (Kuehn, 2014; Besnard, 2018; Buchbinder, 2018; Schwab, 2018; Ayrignac, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.83, 0.87, 0.92
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs606231417; hg19: chr2-204735350; COSMIC: COSV105880934;