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NM_000152.5(GAA):c.1220A>G (p.Tyr407Cys) AND Glycogen storage disease, type II

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 26, 2023
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:
RCV003609728.2

Allele description [Variation Report for NM_000152.5(GAA):c.1220A>G (p.Tyr407Cys)]

NM_000152.5(GAA):c.1220A>G (p.Tyr407Cys)

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.1220A>G (p.Tyr407Cys)
HGVS:
  • NC_000017.11:g.80108722A>G
  • NG_009822.1:g.12167A>G
  • NM_000152.5:c.1220A>GMANE SELECT
  • NM_001079803.3:c.1220A>G
  • NM_001079804.3:c.1220A>G
  • NM_001406741.1:c.1220A>G
  • NM_001406742.1:c.1220A>G
  • NP_000143.2:p.Tyr407Cys
  • NP_000143.2:p.Tyr407Cys
  • NP_001073271.1:p.Tyr407Cys
  • NP_001073272.1:p.Tyr407Cys
  • NP_001393670.1:p.Tyr407Cys
  • NP_001393671.1:p.Tyr407Cys
  • LRG_673t1:c.1220A>G
  • LRG_673:g.12167A>G
  • LRG_673p1:p.Tyr407Cys
  • NC_000017.10:g.78082521A>G
  • NM_000152.3:c.1220A>G
Protein change:
Y407C
Molecular consequence:
  • NM_000152.5:c.1220A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079803.3:c.1220A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079804.3:c.1220A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406741.1:c.1220A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406742.1:c.1220A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Glycogen storage disease, type II (GSD2)
Synonyms:
ACID ALPHA-GLUCOSIDASE DEFICIENCY; GLYCOGENOSIS, GENERALIZED, CARDIAC FORM; GSD II; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009290; MedGen: C0017921; Orphanet: 365; OMIM: 232300

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004537737Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Dec 26, 2023) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Update of the Pompe variant database for the prediction of clinical phenotypes: Novel disease-associated variants, common sequence variants, and results from newborn screening.

de Faria DOS, 't Groen SLMI, Hoogeveen-Westerveld M, Nino MY, van der Ploeg AT, Bergsma AJ, Pijnappel WWMP.

Hum Mutat. 2021 Feb;42(2):119-134. doi: 10.1002/humu.24148. Epub 2020 Dec 21.

PubMed [citation]
PMID:
33560568
PMCID:
PMC7898817

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004537737.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 407 of the GAA protein (p.Tyr407Cys). This variant is present in population databases (rs780674083, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GAA protein function with a positive predictive value of 95%. This variant disrupts the p.Tyr407 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33560568; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Sep 29, 2024