2-203870886-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P137Q) 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.24

Publications

2 publications found

Variant links:

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

CTLA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 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 chr2-203870886-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 574111.

PP5

Variant 2-203870886-C-T is Pathogenic according to our data. Variant chr2-203870886-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 432079.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 link	c.410C>T	p.Pro137Leu	missense_variant	Exon 2 of 4	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3 link	c.410C>T	p.Pro137Leu	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 link	c.410C>T	p.Pro137Leu	missense_variant	Exon 2 of 4		NM_005214.5	ENSP00000497102.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727224

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

Pathogenic:3

Jan 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). For these reasons, this variant has been classified as Pathogenic. -

Feb 23, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4 moderate, PM2, PM5, PP1 moderate, BP4 supporting -

Jul 30, 2024

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

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

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 09, 2016

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Benign

0.074

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.7

M;M;M

PhyloP100

5.2

PrimateAI

Uncertain

0.57

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

GERP RS

5.3

Varity_R

0.90

gMVP

0.90

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over