NM_020988.3(GNAO1):c.662C>A (p.Ala221Asp) AND Neurodevelopmental disorder with involuntary movements

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 15, 2018
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:: RCV000626015.4

Allele description [Variation Report for NM_020988.3(GNAO1):c.662C>A (p.Ala221Asp)]

NM_020988.3(GNAO1):c.662C>A (p.Ala221Asp)

Gene:

GNAO1:G protein subunit alpha o1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q13

Genomic location:

Preferred name:

NM_020988.3(GNAO1):c.662C>A (p.Ala221Asp)

HGVS:

NC_000016.10:g.56336799C>A
NG_042800.1:g.150461C>A
NM_020988.3:c.662C>AMANE SELECT
NM_138736.3:c.662C>A
NP_066268.1:p.Ala221Asp
NP_620073.2:p.Ala221Asp
NC_000016.9:g.56370711C>A
NM_020988.2:c.662C>A
p.A221D

Protein change:

A221D

Links:

dbSNP: rs1555507479

NCBI 1000 Genomes Browser:

rs1555507479

Molecular consequence:

NM_020988.3:c.662C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_138736.3:c.662C>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Neurodevelopmental disorder with involuntary movements (NEDIM)
Identifiers:: MONDO: MONDO:0060491; MedGen: C4479569; OMIM: 617493

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000746624	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 1, 2016)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000924543	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 15, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000746624

Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 1, 2016)

de novo

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000924543

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 15, 2018)

germline

research

PubMed (1)
[See all records that cite this PMID]

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	research
White	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV000746624.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	White	1	not provided	not provided	clinical testing (GTR000553916.1)	PubMed (1)

Description

Our patient has the more recently described phenotype (MIM #617493) associated with de novo heterozygous GNAO1 mutations, which includes developmental delay and movement disorder. Our patient's presentation is milder than those cases reported in the literature to date.

Description

This variant, which is de novo in our patient, is novel (absent from 1000 Genomes, ExAC, gnomAD & Geno2MP databases), and is predicted to be damaging (SIFT, PolyPhen2, MutationTaster), and the patient's clinical presentation is similar to other reported cases. This individual has been reported in PMID: 30682224 (patient 8).

#	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	(GTR000553916.1)	1	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV000924543.1

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

Description

The heterozygous p.Ala221Asp variant was identified by our study, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the UDN, in one individual with neurodevelopmental disorder with involuntary movements. Trio exome analysis showed this variant to be de novo. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to definitively determine pathogenicity. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic.

#	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

Last Updated: Jun 9, 2024

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