NM_000152.5(GAA):c.688G>A (p.Val230Met) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Jun 24, 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:: RCV000724048.14

Allele description [Variation Report for NM_000152.5(GAA):c.688G>A (p.Val230Met)]

NM_000152.5(GAA):c.688G>A (p.Val230Met)

Gene:

GAA:alpha glucosidase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q25.3

Genomic location:

Preferred name:

NM_000152.5(GAA):c.688G>A (p.Val230Met)

HGVS:

NC_000017.11:g.80105890G>A
NG_009822.1:g.9335G>A
NM_000152.5:c.688G>AMANE SELECT
NM_001079803.3:c.688G>A
NM_001079804.3:c.688G>A
NP_000143.2:p.Val230Met
NP_001073271.1:p.Val230Met
NP_001073272.1:p.Val230Met
LRG_673t1:c.688G>A
LRG_673:g.9335G>A
NC_000017.10:g.78079689G>A
NM_000152.3:c.688G>A
NM_000152.4(GAA):c.688G>A
p.Val230Met

Protein change:

V230M

Links:

dbSNP: rs145866792

NCBI 1000 Genomes Browser:

rs145866792

Molecular consequence:

NM_000152.5:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.688G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000228795	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions)	Uncertain significance (Aug 2, 2018)	germline	clinical testing	Citation Link,
SCV000925086	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Uncertain significance (Feb 6, 2018)	germline	provider interpretation
SCV001791057	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 24, 2024)	germline	clinical testing	Citation Link,
SCV003816224	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 8, 2019)	germline	clinical testing	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	unknown	3	not provided	not provided	not provided	not provided	clinical testing, provider interpretation
not provided	germline	yes	not provided	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 Eurofins Ntd Llc (ga), SCV000228795.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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	unknown	not provided	not provided	not provided		3	not provided	not provided	not provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000925086.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	provider interpretation	not provided

Description

Found in a 23-year-old female with unexplained postpartum sudden cardiac arrest, along with 5 other VUSs. p.Val230Met (c.688G>A) in exon 3 of the GAA gene (NM_000152.3) Chromosome location 17-78079689-G-A Based on the information reviewed below, we classify this as a Variant of Uncertain Significance (VUS). This variant has not been reported in the literature in association with disease, according to the Invitae report. Of note: The GAA gene is associated with autosomal recessive glycogen storage disease type II (GSDII), also known as Pompe disease (MedGen UID: 5340). Our adult patient does not display any known clinical symptoms of Pompe, and because this is a recessive condition she would need to have a disease-causing variant in each allele in order to have the condition. This one variant in one allele would not be sufficient, even if it were pathogenic. This is a conservative amino acid change, resulting in the replacement of a nonpolar Valine with a nonpolar Methionine. Valine at this location is highly conserved across ~100 vertebrate species for which we have data. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant was reported in 74 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall MAF: 0.03%. It is most prevalent among individuals with either African or Latino ancestry (like our patient). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.

#	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

From GeneDx, SCV001791057.2

#	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 indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 9425285, 7603530, 19343043, 22253258)

#	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 Revvity Omics, Revvity, SCV003816224.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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