NM_005273.4(GNB2):c.217G>A (p.Ala73Thr) AND Neurodevelopmental disorder with hypotonia and dysmorphic facies

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Mar 14, 2024
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:: RCV001582411.10

Allele description [Variation Report for NM_005273.4(GNB2):c.217G>A (p.Ala73Thr)]

NM_005273.4(GNB2):c.217G>A (p.Ala73Thr)

Gene:

GNB2:G protein subunit beta 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q22.1

Genomic location:

Preferred name:

NM_005273.4(GNB2):c.217G>A (p.Ala73Thr)

HGVS:

NC_000007.14:g.100677365G>A
NM_005273.4:c.217G>AMANE SELECT
NP_005264.2:p.Ala73Thr
NC_000007.13:g.100274988G>A
NM_005273.3:c.217G>A

Protein change:

A73T; ALA73THR

Links:

OMIM: 139390.0004; dbSNP: rs1424516740

Molecular consequence:

NM_005273.4:c.217G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Neurodevelopmental disorder with hypotonia and dysmorphic facies
Identifiers:: MONDO: MONDO:0859185; MedGen: C5561974; OMIM: 619503

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001821514	OMIM	no assertion criteria provided	Pathogenic (Apr 25, 2022)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001994806	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 28, 2021)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002058664	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:34183358,
SCV002574827	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin See additional submitters CUBI - Core Unit Bioinformatics, Berlin Institute of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 22, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004801373	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 14, 2024)	maternal	research	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	maternal	yes	1	not provided	not provided	1	not provided	research
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	2	not provided	not provided	2	not provided	clinical testing

Citations

PubMed

Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability.

Tan NB, Pagnamenta AT, Ferla MP, Gadian J, Chung BH, Chan MC, Fung JL, Cook E, Guter S, Boschann F, Heinen A, Schallner J, Mignot C, Keren B, Whalen S, Sarret C, Mittag D, Demmer L, Stapleton R, Saida K, Matsumoto N, Miyake N, et al.

J Med Genet. 2022 May;59(5):511-516. doi: 10.1136/jmedgenet-2020-107462. Epub 2021 Jun 28.

PubMed [citation]

PMID:: 34183358

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV001821514.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 3 unrelated patients (P1, P2, and P3) with neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF; 619503), Tan et al. (2022) identified a de novo heterozygous c.217G-A transition (c.217G-A, NM_005273.3) in the GNB2 gene, resulting in an ala73-to-thr (A73T) substitution at a conserved residue in a WD40 domain. The mutation was found by genome or exome sequencing. It was present once in the heterozygous state in the gnomAD database (3.2 x 10(-5)), and the authors suggested that the control individual may have had mild developmental delay. The patients reported by Tan et al. (2022) with the A73T mutation had a somewhat milder phenotype compared to patients with other GNB2 mutations.

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

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV001994806.1

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

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

From 3billion, SCV002058664.1

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

Description

The variant has been observed in at least two similarly affected unrelated individuals (PMID: 34183358, PS4_M). The variant has been previously reported as de novo in a similarly affected individual (PMID: 34183358, PS2_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.639, PP3_P). A missense variant is a common mechanism associated with Neurodevelopmental disorder with hypotonia and dysmorphic facies (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000032, PM2_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, SCV002574827.2

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

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

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-SouthSeq, SCV004801373.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

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

Last Updated: Dec 20, 2025

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