NM_000152.5(GAA):c.761C>T (p.Ser254Leu) AND Glycogen storage disease, type II

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Aug 28, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000285433.17

Allele description [Variation Report for NM_000152.5(GAA):c.761C>T (p.Ser254Leu)]

NM_000152.5(GAA):c.761C>T (p.Ser254Leu)

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.761C>T (p.Ser254Leu)

HGVS:

NC_000017.11:g.80107625C>T
NG_009822.1:g.11070C>T
NM_000152.5:c.761C>TMANE SELECT
NM_001079803.3:c.761C>T
NM_001079804.3:c.761C>T
NP_000143.2:p.Ser254Leu
NP_001073271.1:p.Ser254Leu
NP_001073272.1:p.Ser254Leu
LRG_673t1:c.761C>T
LRG_673:g.11070C>T
NC_000017.10:g.78081424C>T
NM_000152.3:c.761C>T
NM_000152.4:c.761C>T
P10253:p.Ser254Leu

Protein change:

S254L

Links:

UniProtKB: P10253#VAR_068579; dbSNP: rs577915581

NCBI 1000 Genomes Browser:

rs577915581

Molecular consequence:

NM_000152.5:c.761C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079803.3:c.761C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079804.3:c.761C>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000407271	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Likely pathogenic (Jun 14, 2016)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21232767, 20080426, 22644586, 18458862, 24513544, 25466677, 27183828 ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000626639	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 28, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24513544, 29124014, 27183828, 22644586, 28492532
SCV001132197	Counsyl	no assertion criteria provided	Likely pathogenic (Jun 11, 2019)	unknown	clinical testing	PubMed (12) [See all records that cite these PMIDs] 28450385, 18458862, 24513544, 22644586, 21232767, 29122469, 27183828, 29124014, 28196920, 20080426, 25466677, 31076647
SCV001528212	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 24, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001810440	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Mass Spectrometry but Not Fluorimetry Distinguishes Affected and Pseudodeficiency Patients in Newborn Screening for Pompe Disease.

Liao HC, Chan MJ, Yang CF, Chiang CC, Niu DM, Huang CK, Gelb MH.

Clin Chem. 2017 Jul;63(7):1271-1277. doi: 10.1373/clinchem.2016.269027. Epub 2017 Apr 27. Erratum in: Clin Chem. 2023 Jun 1;69(6):670. doi: 10.1093/clinchem/hvad023.

PubMed [citation]

PMID:: 28450385
PMCID:: PMC5524447

See all PubMed Citations (14)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000407271.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

#	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 Invitae, SCV000626639.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The c.761C>T sequence change replaces serine with leucine at codon 254 of the GAA protein (p.Ser254Leu). The serine residue is highly conserved and there is a large physiochemical difference between serine and leucine. This variant is present in population databases (rs577915581, gnomAD 0.3%). The c.761C>T (p.Ser254Leu) variant frequently co-occurs with the c.752C>T (p.Ser251Leu) variant (rs200856561) in cis (on the same chromosome), which is known as the c.[752C>T;761C>T] haplotype. This haplotype has been reported in the literature as homozygous or in combination with other GAA variants in multiple individuals affected with Pompe disease (PMID: 24513544, 29124014, 27183828). The clinical significance of the c.761C>T variant alone is unclear. ClinVar contains an entry for this variant (Variation ID: 325782). ClinVar contains an entry for this variant (Variation ID: 325782). While the c.761C>T (p.Ser254Leu) variant alone has not been shown to affect GAA protein function, the c.[752C>T;761C>T] haplotype has been reported to reduce enzyme activity (PMID: 22644586). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this haplotype has been classified as Pathogenic.

#	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 Counsyl, SCV001132197.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

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

From Baylor Genetics, SCV001528212.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

From Genome-Nilou Lab, SCV001810440.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 30, 2024

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