rs587777630

Variant names:

• chr2-190986921-G-A
• rs587777630
• NM_007315.4:c.1154C>T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_007315.4(STAT1):​c.1154C>T​(p.Thr385Met) variant causes a missense change. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T385K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STAT1 NM_007315.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 6.71

Genes affected

STAT1 (HGNC:11362): (signal transducer and activator of transcription 1) The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. The protein encoded by this gene can be activated by various ligands including interferon-alpha, interferon-gamma, EGF, PDGF and IL6. This protein mediates the expression of a variety of genes, which is thought to be important for cell viability in response to different cell stimuli and pathogens. The protein plays an important role in immune responses to viral, fungal and mycobacterial pathogens. Mutations in this gene are associated with Immunodeficiency 31B, 31A, and 31C. [provided by RefSeq, Jun 2020]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-190986921-G-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in the STAT1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 64 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 5.1492 (above the threshold of 3.09). Trascript score misZ: 7.0181 (above the threshold of 3.09). GenCC associations: The gene is linked to Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, immunodeficiency 31B.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907
• PP5: Variant 2-190986921-G-A is Pathogenic according to our data. Variant chr2-190986921-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 144006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-190986921-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAT1	NM_007315.4	c.1154C>T	p.Thr385Met	missense_variant	Exon 14 of 25	ENST00000361099.8	NP_009330.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAT1	ENST00000361099.8	c.1154C>T	p.Thr385Met	missense_variant	Exon 14 of 25	1	NM_007315.4	ENSP00000354394.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Mar 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 08, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2, PP3, PM2, PS2, PS3, PS4 -

Mar 26, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in published literature in individuals with IPEX-like disease (PMID: 28601685); Published functional studies demonstrate a increased activity, consistent with a gain of function: enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1 (PMID: 23541320, 28601685); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26604104, 23709754, 32180118, 32706110, 32477911, 24239102, 23534974, 26743090, 25288569, 22730530, 27379765, 27577878, 28597685, 29270166, 29111217, 29259832, 30443250, 30543054, 28601685, 25042743, 23541320, 31805313, 31767209, 31686315, 31019026, 30092289, 32499645, 32581362, 34060650, 33225392, 33027576, 30755392, 32327459, 32888943, 33475942, 33344614, 35874679, 34738677, 37678716, 34333925, 33005702, 34390440, 34645491, 35482138, 35435464, 36881481, 36790564) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2018

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome Pathogenic:2

Mar 08, 2018

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]. This variant has been previously reported as disease-causing in multiple patients with autosomal dominant immunodeficiency [PMID 22730530, 27379765, 26604104, 28597685, 23541320, 24239102, 27577878, 23534974, 26743090] -

Sep 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

STAT1-related disorder Pathogenic:1

Mar 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The STAT1 c.1154C>T variant is predicted to result in the amino acid substitution p.Thr385Met. This variant has been well-documented to be pathogenic for mucocutaneous candidiasis and immunodeficiency (Takezaki et al. 2012. PubMed ID: 22730530; Depner et al. 2015. PubMed ID: 26604104; Ji et al. 2019. PubMed ID: 30755392). This variant is interpreted as pathogenic by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/144006/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Immunodeficiency 31B;C3279990:Autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome;C4013950:Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency Pathogenic:1

Apr 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 385 of the STAT1 protein (p.Thr385Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant chronic mucocutaneous candidiasis (PMID: 22730530, 23541320, 23709754, 24239102, 25042743, 26604104, 26743090, 27379765, 28597685). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 144006). 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 STAT1 function (PMID: 22730530, 23534974, 23541320, 23709754, 26604104). For these reasons, this variant has been classified as Pathogenic. -

Inherited Immunodeficiency Diseases Pathogenic:1

Jan 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.6	M;M;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.2	D;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.77
MutPred		0.64		Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);.;
MVP		0.96
MPC		2.6
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.67
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587777630; hg19: chr2-191851647; COSMIC: COSV63116411; COSMIC: COSV63116411;