NM_002074.5(GNB1):c.239T>C (p.Ile80Thr) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Aug 10, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000418135.28

Allele description [Variation Report for NM_002074.5(GNB1):c.239T>C (p.Ile80Thr)]

NM_002074.5(GNB1):c.239T>C (p.Ile80Thr)

Gene:

GNB1:G protein subunit beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.33

Genomic location:

Preferred name:

NM_002074.5(GNB1):c.239T>C (p.Ile80Thr)

Other names:

NM_002074.5(GNB1):c.239T>C

HGVS:

NC_000001.11:g.1806503A>G
NG_047052.1:g.89615T>C
NM_001282538.2:c.-62T>C
NM_001282539.2:c.239T>C
NM_002074.5:c.239T>CMANE SELECT
NP_001269468.1:p.Ile80Thr
NP_001269468.1:p.Ile80Thr
NP_002065.1:p.Ile80Thr
NC_000001.10:g.1737942A>G
NM_001282539.1:c.239T>C
NM_002074.3:c.239T>C
NM_002074.4:c.239T>C
P62873:p.Ile80Thr

Protein change:

I80T; ILE80THR

Links:

UniProtKB: P62873#VAR_076648; OMIM: 139380.0002; dbSNP: rs752746786

NCBI 1000 Genomes Browser:

rs752746786

Molecular consequence:

NM_001282538.2:c.-62T>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001282539.2:c.239T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002074.5:c.239T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

effect on protein interaction [Variation Ontology: 0058]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000529467	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 19, 2021)	germline	clinical testing	Citation Link,
SCV001250213	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (May 1, 2018)	germline	clinical testing	Citation Link,
SCV001586058	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 10, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27108799, 25485910, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000529467

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Nov 19, 2021)

germline

clinical testing

Citation Link,

SCV001250213

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(May 1, 2018)

germline

clinical testing

Citation Link,

SCV001586058

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 10, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline De Novo Mutations in GNB1 Cause Severe Neurodevelopmental Disability, Hypotonia, and Seizures.

Petrovski S, Küry S, Myers CT, Anyane-Yeboa K, Cogné B, Bialer M, Xia F, Hemati P, Riviello J, Mehaffey M, Besnard T, Becraft E, Wadley A, Politi AR, Colombo S, Zhu X, Ren Z, Andrews I, Dudding-Byth T, Schneider AL, Wallace G; University of Washington Center for Mendelian Genomics., et al.

Am J Hum Genet. 2016 May 5;98(5):1001-1010. doi: 10.1016/j.ajhg.2016.03.011. Epub 2016 Apr 21.

PubMed [citation]

PMID:: 27108799
PMCID:: PMC4863562

Mutations in G protein β subunits promote transformation and kinase inhibitor resistance.

Yoda A, Adelmant G, Tamburini J, Chapuy B, Shindoh N, Yoda Y, Weigert O, Kopp N, Wu SC, Kim SS, Liu H, Tivey T, Christie AL, Elpek KG, Card J, Gritsman K, Gotlib J, Deininger MW, Makishima H, Turley SJ, Javidi-Sharifi N, Maciejewski JP, et al.

Nat Med. 2015 Jan;21(1):71-5. doi: 10.1038/nm.3751. Epub 2014 Dec 8.

PubMed [citation]

PMID:: 25485910
PMCID:: PMC4289115

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000529467.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 27513193, 27108799, 31142838, 25485910, 30194818, 31036916, 31735425, 32963807, 34096027, 31785789)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001250213.21

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Invitae, SCV001586058.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 80 of the GNB1 protein (p.Ile80Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GNB1-related conditions (PMID: 27108799). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208722). 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) performed at Invitae indicates that this missense variant is expected to disrupt GNB1 protein function. Experimental studies have shown that this missense change affects GNB1 function (PMID: 25485910). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 12, 2024

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