chr2-203870886-C-T

Position:

• chr2-203870886-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_005214.5(CTLA4):​c.410C>T​(p.Pro137Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 5.24

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-203870886-C-T is Pathogenic according to our data. Variant chr2-203870886-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 432079.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.410C>T	p.Pro137Leu	missense_variant	2/4	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3	c.410C>T	p.Pro137Leu	missense_variant	2/3		NP_001032720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000648405.2	c.410C>T	p.Pro137Leu	missense_variant	2/4		NM_005214.5	ENSP00000497102.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727224

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

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Feb 23, 2021	ACMG classification criteria: PS4 moderate, PM2, PM5, PP1 moderate, BP4 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jul 30, 2024	The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). n silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.86 (>=0.6, sensitivity 0.72 and precision 0.9)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000432079). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 26884280, 27102614, 27577878, 30377434, 30940614). A different missense change at the same codon (p.Pro137Arg) has been reported to be associated with CTLA4-related disorder (ClinVar ID: VCV000827701 / PMID: 27102614). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 432079). This missense change has been observed in individuals with clinical features of CTLA4 haploinsufficiency (PMID: 26884280, 27102614, 27577878, 30377434, 30940614; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 137 of the CTLA4 protein (p.Pro137Leu). -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

CTLA4 NM_005214.4 exon 2 p.Pro137Leu (c.410C>T): This variant has been reported in the literature in at least 2 individuals with immunodeficiency, 1 of whom presented with a complex phenotype including autoimmune cytopenias, enteropathy, pancreatic insufficiency, diabetes and renal insufficiency (Slatter 2016 PMID:27102614, Stray-Pederson 2016 PMID:27577878). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:432079). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, other variants at this codon have been reported in association with disease (p.Pro137Arg, p.Pro137Gln) suggesting that this region has significance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2016

The P137L variant in the CTLA4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The P137L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P137L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret P137L as a likely pathogenic variant -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.7	M;M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-8.3	.;D;D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	D;D;.
Vest4		0.80, 0.81
MVP		0.69
MPC		1.7
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1553657429; hg19: chr2-204735609; COSMIC: COSV99865235;