rs143347747

chr17-80117663-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000152.5(GAA):c.2395C>T(p.His799Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,612,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:9
• Conservation: PhyloP100: 1.22

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28149402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.2395C>T	p.His799Tyr	missense_variant	17/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.2395C>T	p.His799Tyr	missense_variant	17/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000362 AC: 9 AN: 248542 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135046

Gnomad AFR exome AF: 0.000376

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

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: 0.00000959 AC: 14 AN: 1460582 Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5 AN XY: 726604

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74474

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Sep 05, 2023	The NM_000152.5:c.2395C>T variant in GAA is a missense variant predicted to cause substitution of His by Tyr at amino acid 799 (p.His799Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00038 (6/15954 alleles) in the African population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.443 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). It only has been reported in one case as LOPD, in which has unknown phase concurrence in compound heterozygous with c.-32-13T>G (PMID: 22958975). Thus met PM3_supporting. The LOPD case has been reported to have GAA residue level 0.25 (normal cutoff unknown. But average of 20 LOPD patients is 8.35, so <10% of normal mean control level). Thus PP4_moderate is applied. There is a ClinVar entry for this variant (Variation ID: 284886, 2 star review status) with 8 submitters classifying the variant as Uncertain significance with no conflicts. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP4_moderate, PM3_supporting, BP4. (Classification approved by the ClinGen Lysosomal Diseases VCEP, September 5, 2023) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 22, 2022	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 799 of the GAA protein (p.His799Tyr). This variant is present in population databases (rs143347747, gnomAD 0.03%). This missense change has been observed in individual(s) with Pompe disease (PMID: 22958975). ClinVar contains an entry for this variant (Variation ID: 284886). 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 not expected to disrupt GAA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 07, 2023	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.His799Tyr variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been identified in 0.038% (6/15954) of African chromosomes, 0.006% (2/34532) of Latino chromosomes, and 0.005% (1/18354) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs143347747). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a VUS by EGL Genetic Diagnostics and Invitae in ClinVar (Variation ID: 284886). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The Histidine (His) at position 799 is not highly conserved in mammals and evolutionary distant species, and 5 species (nile tilapia, princess of Burundi, burton's mouthbreather, zebra mbuna, pundamilia nyererei) carry a Tyrosine (Tyr), raising the possibility that this change at this position may be tolerated. In summary, the clinical significance of the p.His799Tyr variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4 (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 27, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 31, 2015	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 01, 2022

Variant summary: GAA c.2395C>T (p.His799Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 150978 control chromosomes, predominantly within the Latino and African subpopulations at a frequency of 0.00092 and 0.00031, respectively, in the gnomAD database (v3.1 genomes dataset). These frequencies are not significantly higher than the estimated maximum expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.0042), allowing no conclusion about variant significance. The variant, c.2395C>T, has been reported in the literature in a compound heterozygote individual affected with the late form of Glycogen Storage Disease Type 2 (Pompe Disease) (Musumeci_2012), however, in a later report this patient was noted to carry two co-occurring (potentially) pathogenic variants, which could explain the phenotype, although the phase of the three variants was not specified (Montagnese_2015). These reports do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	15
Dann	Benign	0.92
DEOGEN2	Uncertain	0.61	D;D
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.13	N;N
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.58	N;N
REVEL	Uncertain	0.44
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0060	B;B
Vest4		0.69
MVP		0.75
MPC		0.13
ClinPred		0.021	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs143347747; hg19: chr17-78091462;