NM_002074.5(GNB1):c.154C>T (p.Arg52Trp) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 3, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV002464488.5

Allele description [Variation Report for NM_002074.5(GNB1):c.154C>T (p.Arg52Trp)]

NM_002074.5(GNB1):c.154C>T (p.Arg52Trp)

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.154C>T (p.Arg52Trp)

HGVS:

NC_000001.11:g.1815805G>A
NG_047052.1:g.80313C>T
NM_001282538.2:c.-97-9267C>T
NM_001282539.2:c.154C>T
NM_002074.5:c.154C>TMANE SELECT
NP_001269468.1:p.Arg52Trp
NP_002065.1:p.Arg52Trp
NC_000001.10:g.1747244G>A
NM_002074.4:c.154C>T

Protein change:

R52W

Links:

dbSNP: rs2100858748

NCBI 1000 Genomes Browser:

rs2100858748

Molecular consequence:

NM_001282538.2:c.-97-9267C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001282539.2:c.154C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002074.5:c.154C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002759145	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jun 3, 2022)	germline	clinical testing	Citation Link,
SCV003348973	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 4, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28087732, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002759145

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jun 3, 2022)

germline

clinical testing

Citation Link,

SCV003348973

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 4, 2022)

germline

clinical testing

PubMed (2)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans.

Lohmann K, Masuho I, Patil DN, Baumann H, Hebert E, Steinrücke S, Trujillano D, Skamangas NK, Dobricic V, Hüning I, Gillessen-Kaesbach G, Westenberger A, Savic-Pavicevic D, Münchau A, Oprea G, Klein C, Rolfs A, Martemyanov KA.

Hum Mol Genet. 2017 Mar 15;26(6):1078-1086. doi: 10.1093/hmg/ddx018.

PubMed [citation]

PMID:: 28087732
PMCID:: PMC6075543

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV002759145.1

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

Description

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; Has not been previously published as pathogenic or benign to our knowledge

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003348973.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 52 of the GNB1 protein (p.Arg52Trp). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg52 amino acid residue in GNB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28087732). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 1326280). This variant has not been reported in the literature in individuals affected with GNB1-related conditions. This variant is not present in population databases (gnomAD no frequency).

#	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: Oct 13, 2024

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