Submissions for variant NM_000152.5(GAA):c.2003A>G (p.Tyr668Cys)

dbSNP: rs1555601633

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV001379709	SCV004042614	uncertain significance	Glycogen storage disease, type II	2023-09-05	reviewed by expert panel	curation	The NM_000152.5:c.2003A>G variant in GAA is a missense variant predicted to cause substitution of Tyr by Cys at amino acid 668 (p.Tyr668Cys). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.929 which is above the thresholds predicting a damaging (>0.7) impact on GAA function. Thus met PP3 criteria. It has been reported in one case with Low AaGlu activity in DBS and fibroblast (PMID 31076647, 33073027, 34922579). There are four other newborn screening cases (from 2 clinical laboratories data) with deficiency of GAA activity. All 5 cases are free of Pompe symptoms. Thus PP4 is met. One of these cases has pathogenic allele c.752C>T+c.761C>T and common pseudodeficiency alleles c.1726G>A and c.2065G>A (PMID 31076647, 33073027, 34922579). Two of the cases has pathogenic allele c.-32-13T>G in trans. Another case also has c.-32-13T>G allele (clinical laboratory data) with phase unknown. Thus PM3 is met. There is a ClinVar entry for this variant (Variation ID: 546808, 1 star review status) with 2 submitters classifying the variant as Uncertain significance, 1 submitter classifying it as Pathogenic, and 1 submitter classifying it as Likely Pathogenic. 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, PM3, PP3. (Classification approved by the ClinGen Lysoosomal Diseases VCEP, September 5, 2023)
CeGaT Center for Human Genetics Tuebingen	RCV000658795	SCV000780590	uncertain significance	not provided	2018-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV001379709	SCV001577557	pathogenic	Glycogen storage disease, type II	2023-07-15	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pompe disease (PMID: 31076647; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 546808). 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. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 668 of the GAA protein (p.Tyr668Cys).
Genome-Nilou Lab	RCV001379709	SCV001810639	likely pathogenic	Glycogen storage disease, type II	2021-07-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000658795	SCV003828457	uncertain significance	not provided	2022-04-14	criteria provided, single submitter	clinical testing