NM_000152.5(GAA):c.2238G>C (p.Trp746Cys) AND Cardiovascular phenotype

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 22, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004021024.1

Allele description [Variation Report for NM_000152.5(GAA):c.2238G>C (p.Trp746Cys)]

NM_000152.5(GAA):c.2238G>C (p.Trp746Cys)

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.2238G>C (p.Trp746Cys)

Other names:

NM_000152.3(GAA):c.2238G>C(p.Trp746Cys); NM_001079803.1(GAA):c.2238G>C(p.Trp746Cys); NM_001079804.1(GAA):c.2238G>C(p.Trp746Cys)

HGVS:

NC_000017.11:g.80117016G>C
NG_009822.1:g.20461G>C
NM_000152.4(GAA):c.2238G>C
NM_000152.5:c.2238G>CMANE SELECT
NM_001079803.3:c.2238G>C
NM_001079804.3:c.2238G>C
NP_000143.2:p.Trp746Cys
NP_001073271.1:p.Trp746Cys
NP_001073272.1:p.Trp746Cys
LRG_673t1:c.2238G>C
LRG_673:g.20461G>C
NC_000017.10:g.78090815G>C
NM_000152.3:c.2238G>C
NM_000152.4(GAA):c.2238G>C
NM_000152.4:c.2238G>C
NM_001079803.1:c.2238G>C
NM_001079803.2:c.2238G>C
NM_001079804.3:c.2238G>C
P10253:p.Trp746Cys

Protein change:

W746C

Links:

UniProtKB: P10253#VAR_004311; dbSNP: rs1800312

NCBI 1000 Genomes Browser:

rs1800312

Molecular consequence:

NM_000152.5:c.2238G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.2238G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.2238G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005032503	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (18) [See all records that cite these PMIDs] 18458862, 21232767, 21757382, 23430493, 25093132, 25526786, 27099502, 27363342, 27692865, 28433475, 29451150, 30360039, 32126021, 33202836, 33673364, 35071497, 35386406, 35795986 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005032503

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 22, 2024)

germline

clinical testing

PubMed (18)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of eight novel mutations of the acid alpha-glucosidase gene causing the infantile or juvenile form of glycogen storage disease type II.

Wan L, Lee CC, Hsu CM, Hwu WL, Yang CC, Tsai CH, Tsai FJ.

J Neurol. 2008 Jun;255(6):831-8. doi: 10.1007/s00415-008-0714-0. Epub 2008 May 6.

PubMed [citation]

PMID:: 18458862

Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening.

Chien YH, Lee NC, Huang HJ, Thurberg BL, Tsai FJ, Hwu WL.

J Pediatr. 2011 Jun;158(6):1023-1027.e1. doi: 10.1016/j.jpeds.2010.11.053. Epub 2011 Jan 13.

PubMed [citation]

PMID:: 21232767

See all PubMed Citations (18)

Details of each submission

From Ambry Genetics, SCV005032503.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

The p.W746C pathogenic mutation (also known as c.2238G>C), located in coding exon 15 of the GAA gene, results from a G to C substitution at nucleotide position 2238. The tryptophan at codon 746 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the compound heterozygous and homozygous states in individuals with Pompe disease, mainly late onset disease (Wan L et al. J Neurol, 2008 Jun;255:831-8; Chien YH et al. J Pediatr, 2011 Jun;158:1023-1027.e1; Yang CC et al. Mol Genet Metab, 2011 Nov;104:284-8; Fu Liong H et al. Case Rep Neurol Med, 2014 Jun;2014:926510; Liu X et al. BMC Med Genet, 2014 Dec;15:141; Chu YP et al. Neuromuscul Disord, 2016 Dec;26:873-879; Zhang B et al. Neuropsychiatr Dis Treat, 2016 Mar;12:713-7; Lee JH et al. Neuromuscul Disord, 2017 Jun;27:550-556; Park HJ et al. Clin Genet, 2017 Mar;91:403-410; Kim MS et al. Korean J Pediatr, 2019 Jun;62:224-234; Ficicioglu C et al. Int J Neonatal Screen, 2020 Nov;6:[ePub ahead of print]; Jia X et al. Aging (Albany NY), 2020 Mar;12:4268-4282; Sudrié-Arnaud B et al. Diagnostics (Basel), 2021 Feb;11:[ePub ahead of print]; Zhao HH et al. Ann Transl Med, 2021 Dec;9:1803; Si X et al. CNS Neurosci Ther, 2022 Oct;28:1651-1654; Zhang H et al. Front Neurol, 2022 Mar;13:839263). This alteration has also been shown to reduce enzyme activity in both patient-derived cells and transfected cells (Niño MY et al. JIMD Rep, 2013 Apr;7:39-48; Liu HX et al. Chin Med J (Engl), 2018 Feb;131:448-453). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 20, 2024

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