rs483352867

Variant names:

• chr11-4074620-C-T
• rs483352867
• NM_001382567.1:c.910C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001382567.1(STIM1):​c.910C>T​(p.Arg304Trp) variant causes a missense 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R304R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STIM1 NM_001382567.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: -0.278
• Publications: 70 publications found

Genes affected

STIM1 (HGNC:11386): (stromal interaction molecule 1) This gene encodes a type 1 transmembrane protein that mediates Ca2+ influx after depletion of intracellular Ca2+ stores by gating of store-operated Ca2+ influx channels (SOCs). It is one of several genes located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocrotical carcinoma, and lung, ovarian, and breast cancer. This gene may play a role in malignancies and disease that involve this region, as well as early hematopoiesis, by mediating attachment to stromal cells. Mutations in this gene are associated with fatal classic Kaposi sarcoma, immunodeficiency due to defects in store-operated calcium entry (SOCE) in fibroblasts, ectodermal dysplasia and tubular aggregate myopathy. This gene is oriented in a head-to-tail configuration with the ribonucleotide reductase 1 gene (RRM1), with the 3' end of this gene situated 1.6 kb from the 5' end of the RRM1 gene. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

STIM1 Gene-Disease associations (from GenCC):

• myopathy, tubular aggregate, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Stormorken syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• tubular aggregate myopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• combined immunodeficiency due to STIM1 deficiency

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant 11-4074620-C-T is Pathogenic according to our data. Variant chr11-4074620-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 132887.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
STIM1	NM_001382567.1	c.910C>T	p.Arg304Trp	missense_variant	Exon 7 of 13	ENST00000526596.2	NP_001369496.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STIM1	ENST00000526596.2	c.910C>T	p.Arg304Trp	missense_variant	Exon 7 of 13	5	NM_001382567.1	ENSP00000433266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Stormorken syndrome Pathogenic:2 Other:1

Aug 28, 2012

Department of Medical Genetics, Oslo University Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Missense mutation found to segregate with Stormorken syndrome (OMIM 185070) in four families -

-

Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jun 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that this variant impairs the function of STIM1 (PMID: 24591628); Not observed at significant frequency 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: 34440373, 32234795, 29483506, 30374325, 26436962, 30390422, 36749824, 4085141, 37903816, 31785581, 35724962, 25044882, 31216405, 33073872, 24591628, 30576443, 29146883, 28624464, 24619930, 25577287) -

Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency Pathogenic:1

Dec 31, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Myopathy with tubular aggregates;C1861451:Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency Pathogenic:1

May 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 304 of the STIM1 protein (p.Arg304Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant STIM1-related conditions (PMID: 24591628, 24619930, 25044882, 25577287, 26436962). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 132887). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STIM1 protein function. Experimental studies have shown that this missense change affects STIM1 function (PMID: 24591628, 25044882). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;T;.;T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.49	N
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.1	M;.;M;.
PhyloP100		-0.28
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.7	D;.;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.87
MutPred		0.24		Loss of phosphorylation at T307 (P = 0.0613);Loss of phosphorylation at T307 (P = 0.0613);Loss of phosphorylation at T307 (P = 0.0613);.;
MVP		0.76
MPC		1.2
ClinPred		0.99	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.82
gMVP		0.40
Mutation Taster		=19/81	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs483352867; hg19: chr11-4095850; COSMIC: COSV56153389; COSMIC: COSV56153389;