rs387906759

Positions:

• chr2-190995205-G-A
• chr2-190995205-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_007315.4(STAT1):​c.800C>T​(p.Ala267Val) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A267A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STAT1 NM_007315.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.56

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 17 ACMG points.

• PM1: In a coiled_coil_region (size 181) in uniprot entity STAT1_HUMAN there are 67 pathogenic changes around while only 4 benign (94%) in NM_007315.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, STAT1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 2-190995205-G-A is Pathogenic according to our data. Variant chr2-190995205-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 30084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-190995205-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STAT1	NM_007315.4	c.800C>T	p.Ala267Val	missense_variant	10/25	ENST00000361099.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STAT1	ENST00000361099.8	c.800C>T	p.Ala267Val	missense_variant	10/25	1	NM_007315.4	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2022	Reported in unrelated individuals with autosomal dominant STAT1-related immunodeficiency in the published literature (van de Veerdonk et al., 2011; Mizoguchi et al., 2014; Depner et al., 2016; Breuer et al., 2017); Published functional studies demonstrate that A267V leads to increased STAT1 phosphorylation, increased DNA binding and transactivation, and impaired STAT3 activity (Sampaio et al., 2013; Zheng et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28161409, 26494717, 26255980, 28815025, 28427548, 26604104, 21714643, 30187709, 32146551, 32888943, 24343863, 23541320) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jun 21, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated, PP1 strong, PP2 supporting -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2013	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 267 of the STAT1 protein (p.Ala267Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant chronic mucocutaneous candidiasis (PMID: 21714643, 23709754, 24343863, 26255980, 26494717, 26604104). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30084). 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: 23541320, 26255980). For these reasons, this variant has been classified as Pathogenic. -

Mendelian susceptibility to mycobacterial diseases due to partial STAT1 deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 12, 2018

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as a pathogenic variant with gain-of-function disease mechanisms [PMID 21714643, 28427548, 28161409, 26604104, 28815025, 24343863, 26494717, 23541320, 26255980] -

Chronic mucocutaneous candidiasis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 04, 2018

The p.Ala267Val variant in STAT1 has been reported in >10 individuals with chron ic mucocutaneous candidiasis (CMC) and segregated with disease in 16 individuals from 9 families (Liu 2011, van de Veerdonk 2011, Sampaio 2013, Mizoguchi 2014, Nielsen 2015, Zheng 2015, Depner 2016, Breuer 2017, Dadak 2017). It was absent f rom large population studies. Additionally, in vitro functional studies support a pathogenic role (Sampaio 2013, Mizoguchi 2014, Zheng 2015). In summary, the p. Ala267Val variant meets criteria to be classified as pathogenic for CMC in an au tosomal dominant manner. ACMG/AMP Criteria applied: PP1_Strong; PM2; PS4_Moderat e; PP3; PS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;.;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.1	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.047	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.86
MutPred		0.76		Loss of catalytic residue at A267 (P = 0.0958);Loss of catalytic residue at A267 (P = 0.0958);Loss of catalytic residue at A267 (P = 0.0958);.;
MVP		0.91
MPC		2.5
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.76
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs387906759; hg19: chr2-191859931; COSMIC: COSV61189771; COSMIC: COSV61189771;