NM_002074.5(GNB1):c.229G>A (p.Gly77Ser) AND not provided

Clinical significance:Pathogenic (Last evaluated: May 1, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:

Allele description [Variation Report for NM_002074.5(GNB1):c.229G>A (p.Gly77Ser)]

NM_002074.5(GNB1):c.229G>A (p.Gly77Ser)

GNB1:G protein subunit beta 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_002074.5(GNB1):c.229G>A (p.Gly77Ser)
  • NC_000001.11:g.1806513C>T
  • NG_047052.1:g.89605G>A
  • NM_001282538.2:c.-72G>A
  • NM_001282539.1:c.229G>A
  • NM_001282539.2:c.229G>A
  • NM_002074.5:c.229G>AMANE SELECT
  • NP_001269468.1:p.Gly77Ser
  • NP_001269468.1:p.Gly77Ser
  • NP_002065.1:p.Gly77Ser
  • NC_000001.10:g.1737952C>T
  • NC_000001.10:g.1737952C>T
  • NM_002074.3:c.229G>A
  • NM_002074.4:c.229G>A
  • P62873:p.Gly77Ser
Protein change:
UniProtKB: P62873#VAR_076645; dbSNP: rs758432471
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001282538.2:c.-72G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001282539.1:c.229G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282539.2:c.229G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002074.5:c.229G>A - missense variant - [Sequence Ontology: SO:0001583]


MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV001584609Invitaecriteria provided, single submitter
(May 1, 2018)
germlineclinical testing

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

SCV001747424CeGaT Praxis fuer Humangenetik Tuebingencriteria provided, single submitter
(May 1, 2021)
germlineclinical testing

Citation Link,

SCV001769566GeneDxcriteria provided, single submitter
(Apr 15, 2021)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyes1not providednot providednot providednot providedclinical testing



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]

Acute lymphoblastic leukemia in a child with a de novo germline gnb1 mutation.

Brett M, Lai AH, Ting TW, Tan AM, Foo R, Jamuar S, Tan EC.

Am J Med Genet A. 2017 Feb;173(2):550-552. doi: 10.1002/ajmg.a.38026. Epub 2016 Oct 19. No abstract available.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001584609.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)


This sequence change replaces glycine with serine at codon 77 of the GNB1 protein (p.Gly77Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported to be de novo in individuals affected with GNB1-related neurodevelopmental delay and hypotonia (PMID: 27108799, Invitae). ClinVar contains an entry for this variant (Variation ID: 224713). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The p.Gly77 amino acid residue in GNB1 has been determined to be clinically significant (PMID: 27759915). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From CeGaT Praxis fuer Humangenetik Tuebingen, SCV001747424.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

From GeneDx, SCV001769566.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided


Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30504930, 29174093, 27759915, 27108799)

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 24, 2021

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