Submissions for variant NM_000152.5(GAA):c.1019A>G (p.Tyr340Cys)

gnomAD frequency: 0.00024  dbSNP: rs144857480

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001039032	SCV004042616	uncertain significance	Glycogen storage disease, type II	2023-08-01	reviewed by expert panel	curation	The NM_000152.5(GAA):c.1019A>G variant in GAA is a missense variant predicted to cause substitution of tyrosine by cysteine at amino acid 340 (p.Tyr340Cys). This variant has been detected in at least 4 individuals with Pompe disease and at least 2 patients with this variant had documented GAA deficiency with activity in the affected range in dried blood spot (internal lab data). Of those individuals, 3 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and 1 was confirmed in trans by parental testing, including c.-32-13T>G (1 patient, internal lab data, confirmed in trans), c.2560C>T; p.Arg854* (1 patient, internal lab data, phase unknown), and c.1292_1295dup p.(Gln433Alafs *74) (1 patient, PMID: 32802993, phase unknown and no follow up to NBS). In addition, one patient is compound heterozygous for the variant and c.1725C>T (p.Tyr575Tyr) (internal lab data), which is not classified as P/LP and one patient was compound heterozygous for the variant and c.2432delT (p.Leu811Argfs*37) (internal lab data, confirmed in trans), but enzyme testing was in the carrier range (PM3 and PP4_Moderate). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00084 (28/282466 alleles) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.752 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). There is a ClinVar entry for this variant (Variation ID: 289356, 2 star review status) with 7 submitters classifying the variant as a variant of uncertain significance. In summary, while this variant meets the criteria to be classified as likely pathogenic for Pompe disease, the GAA VCEP does not believe there is insufficient phenotypic evidence to support this classification at this time. Therefore, this variant will be classified as a variant of uncertain significance until further evidence is available. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VAriant Curation Expert Panel (Specifications Version 2.0): PM3, PP4_Moderate, PP3, PM2_Supporting. Classification approved by the ClinGen Lysosomal Diseases VCEP, August 1st, 2023).
Eurofins Ntd Llc (ga)	RCV000726314	SCV000343704	uncertain significance	not provided	2018-05-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000726314	SCV000618156	uncertain significance	not provided	2021-03-24	criteria provided, single submitter	clinical testing
Invitae	RCV001039032	SCV001202538	uncertain significance	Glycogen storage disease, type II	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 340 of the GAA protein (p.Tyr340Cys). This variant is present in population databases (rs144857480, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 289356). 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. 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.
Genome-Nilou Lab	RCV001039032	SCV002027249	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469100	SCV002765937	uncertain significance	not specified	2022-11-30	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1019A>G (p.Tyr340Cys) results in a non-conservative amino acid change in 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 6e-05 in 251104 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (6e-05 vs 0.0042), allowing no conclusion about variant significance. c.1019A>G has been reported in the literature in patients with unknown phenotypes (Sanders_2020, Tang_2020). 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000726314	SCV003810591	uncertain significance	not provided	2022-07-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001039032	SCV004562623	uncertain significance	Glycogen storage disease, type II	2023-10-13	criteria provided, single submitter	clinical testing	The GAA c.1019A>G; p.Tyr340Cys variant (rs144857480) is reported in the literature in individuals with suspected Pompe disease identified by newborn screening (Sanders 2020, Tang 2020). This variant is reported in ClinVar (Variation ID: 289356) and is found in the African/African-American population with an allele frequency of 0.08% (21/24,922 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.752). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Sanders KA et al. A Comparative Effectiveness Study of Newborn Screening Methods for Four Lysosomal Storage Disorders. Int J Neonatal Screen. 2020 Jun;6(2):44. PMID: 32802993. Tang H et al. The First Year Experience of Newborn Screening for Pompe Disease in California. Int J Neonatal Screen. 2020 Feb 7;6(1):9. PMID: 33073007.
Natera, Inc.	RCV001039032	SCV001455599	uncertain significance	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing