rs577915581

Positions:

chr17-80107625-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_000152.5(GAA):c.761C>T(p.Ser254Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000769 in 1,613,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:4

Conservation

PhyloP100: 5.99

Variant links:

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

GAA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-80107625-C-T is Pathogenic according to our data. Variant chr17-80107625-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 325782.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=2, Likely_pathogenic=3}. Variant chr17-80107625-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.761C>T	p.Ser254Leu	missense_variant	4/20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.761C>T	p.Ser254Leu	missense_variant	4/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000207

AC:

AN:

251124

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00283

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000767

AC:

112

AN:

1460904

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

726776

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00270

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00212

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000756

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:5Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 24, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 19, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jun 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 28, 2022	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. -

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 28, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 22, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29122469, 18458862, 25466677, 27183828, 24513544, 29451150, 29124014, 31637888, 31980526) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 19, 2024

Variant summary: GAA c.761C>T (p.Ser254Leu) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 282470 control chromosomes, predominantly at a frequency of 0.0028 within the East Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00019 vs 0.0042), allowing no conclusion about variant significance. c.761C>T has been reported in the literature as a complex allele in cis with c.752C>T (p.Ser251Leu) in settings of newborn screening for Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Labrousse_2010, Chien_2011, Liao_2014). This complex allele has been observed as a homozygous and compound heterozygous genotype in the ascertained reports among newborns with screening enzyme activity below the cutoff value (example, Liao_2014). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Glycogen Storage Disease, Type 2 (Pompe Disease). Co-occurrences of this complex allele in cis with other pathogenic variant(s) have been reported in the literature (GAA c.1411_1414del, p.E471PfsX5), providing supporting evidence for a benign role (example, Larousse_2010, Liao_2014, Yue_2024). To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31228295, 21232767, 22644586, 20080426, 24513544, 38186848). ClinVar contains an entry for this variant (Variation ID: 325782). Based on the evidence outlined above, the variant was classified as uncertain significance. -

GAA-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2024

The GAA c.761C>T variant is predicted to result in the amino acid substitution p.Ser254Leu. This variant has been reported in individuals with glycogen storage disease 2, also called Pompe Disease (Tang et al. 2020. PubMed ID: 33073007; Fukuhara et al. 2017. PubMed ID: 29124014; Peng et al. 2016. PubMed ID: 27183828; Lee et al. 2019. PubMed ID: 31637888). This variant is reported in 0.28% of alleles in individuals of East Asian descent in gnomAD. The c.761C>T variant frequently occurs in cis with the c.752C>T (p.Ser251Leu) variant, and is known as the c.[752C>T;761C>T] haplotype. This haplotype has been reported in the homozygous or compound heterozygous state in multiple individuals with Pompe disease (Fukuhara et al. 2017. PubMed ID: 29124014; Peng et al. 2016. PubMed ID: 27183828). Of note, the c.[752C>T; 761C>T] (p.[Ser251Leu; Ser254Leu]) haplotype has been reported to be in cis with the c.1411_1414delGAGA variant (Labrousse et al. 2009. PubMed ID: 20080426; Chien et al. 2014. PubMed ID: 25466677; Mori et al. 2017. PubMed ID: 29122469). The c.[752C>T;761C>T] haplotype has been reported to significantly reduce GAA enzyme activity to 1.7-3.3% of wild-type activity (Kroos M et al 2012. PubMed ID: 22644586). ClinVar classifications for the c.761C>T variant range from uncertain, to likely pathogenic, to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/325782/), while one lab has classified the c.[752C>T;761C>T] haplotype as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/1321358/). Although we suspect that this variant may be pathogenic, at this time the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;D;D

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;.;D

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.081

T;T;T

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.1

.;H;H

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-4.8

.;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0020

.;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.85, 0.85

MutPred

0.45

Gain of stability (P = 0.0205);Gain of stability (P = 0.0205);Gain of stability (P = 0.0205);

MVP

1.0

MPC

0.48

ClinPred

0.35

GERP RS

5.1

Varity_R

0.92

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.27

Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over