rs1555599960

Positions:

chr17-80108323-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4PM2PVS1

This summary comes from the ClinGen Evidence Repository: This variant, c.989G>A (p.Trp330Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. Two individuals with Pompe disease and meeting the ClinGen LSD VCEP's specifications for PP4 have been reported in the literature. These individuals are non-identical twins and are compound heterozyous for the variant and c.1655T>C (p.Leu552Pro); this in trans data was used in the assessment of p.Leu552Pro and therefore was not included here in order to avoid a circular argument. Another individual was reported to be compound heterozygous for the variant and c.-32-13T>G (PMID 29880332). While this patient was described as having reduced GAA activity in dried blood spots, the normal range for the assay was not provided and therefore this data was not included. The variant is absent in gnomAD v2.1.1, meeting PM2. There is a ClinVar entry for this variant (Variation ID 550355; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG-AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA401364487/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GAA
NM_000152.5 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:5

Conservation

PhyloP100: 7.56

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

PM2

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.989G>A	p.Trp330Ter	stop_gained	6/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.989G>A	p.Trp330Ter	stop_gained	6/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461372

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Apr 21, 2020	This variant, c.989G>A (p.Trp330Ter), is a nonsense variant that is predicted to result in nonsense mediated decay and lack of gene product, meeting PVS1. Two individuals with Pompe disease and meeting the ClinGen LSD VCEP's specifications for PP4 have been reported in the literature. These individuals are non-identical twins and are compound heterozyous for the variant and c.1655T>C (p.Leu552Pro); this in trans data was used in the assessment of p.Leu552Pro and therefore was not included here in order to avoid a circular argument. Another individual was reported to be compound heterozygous for the variant and c.-32-13T>G (PMID 29880332). While this patient was described as having reduced GAA activity in dried blood spots, the normal range for the assay was not provided and therefore this data was not included. The variant is absent in gnomAD v2.1.1, meeting PM2. There is a ClinVar entry for this variant (Variation ID 550355; 1 star review status) with one submitter classifying the variant as likely pathogenic. In summary, the variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG-AMP criteria met, based on the specifications of the ClinGen LSD VCEP: PVS1, PM2, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 15, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change creates a premature translational stop signal (p.Trp330*) in the GAA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781, 22252923). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Pompe disease (PMID: 12923862). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 550355). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 10, 2017	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 06, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Reported in ClinVar as pathogenic by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel (ClinVar Variant ID#550355; SCV001371765.1 ); This variant is associated with the following publications: (PMID: 25525159, 18425781, 22252923, 12923862, 29880332) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

A;A

Vest4

0.94

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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