Submissions for variant NM_000152.5(GAA):c.265C>T (p.Arg89Cys)

gnomAD frequency: 0.00001  dbSNP: rs534192892

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000553278	SCV002817439	uncertain significance	Glycogen storage disease, type II	2023-01-02	reviewed by expert panel	curation	The NM_000152.5:c.265C>T variant in GAA is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 89 (p.Arg89Cys). At least 1 proband with this variant had documented GAA deficiency with activity in the affected range in dried blood spot was reported (clinical laboratory data). The patient is heterozygous for the pseudodeficiency variant(s) c.271G>A (p.Asp91Asn) and therefore the GAA activity cannot be used for PP4. The proband is compound heterozygous for the variant and a variant classified as Pathogenic by the ClinGen LSD VCEP, c.307T>G (p.Cys103Gly); the variants are confirmed in trans by parental testing. However, the phase of the pseudodeficiency variant is unknown so PM3 was not applied. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.001898 (58/30556 alleles) in the South Asian population (none of the population data codes are met). The computational predictor REVEL gives a score of 0.861 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). One other missense variant, c.266G>A (p.Arg89His) (ClinVar Variation ID: 283219) has been reported in patients with Pompe disease (PMID: 28196920, 28600779, 25626711, 33202836). However, this variant has been classified as a variant of uncertain significance by the ClinGen LSD VCEP and, therefore, this evidence is not sufficient to meet PM5 at any strength. There is a ClinVar entry for this variant (Variation ID: 456412; 1 star review status) with one submitter classifying the variant as Likely Pathogenic and 5 as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Storage Disorders Variant Curation Expert panel (specifications Version 2.0): PP3. (Classification approved by the ClinGen LSD VCEP on December 20, 2022)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553278	SCV000626590	likely pathogenic	Glycogen storage disease, type II	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 89 of the GAA protein (p.Arg89Cys). This variant is present in population databases (rs534192892, gnomAD 0.2%). This missense change has been observed in individual(s) with a positive newborn screening result for GAA-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 456412). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg89 amino acid residue in GAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25626711). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000553278	SCV000895136	uncertain significance	Glycogen storage disease, type II	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001557806	SCV001779639	uncertain significance	not provided	2019-11-05	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV000553278	SCV002027207	uncertain significance	Glycogen storage disease, type II	2021-09-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821499	SCV002072179	uncertain significance	not specified	2017-11-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001557806	SCV003828484	uncertain significance	not provided	2023-12-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000553278	SCV002091900	uncertain significance	Glycogen storage disease, type II	2020-01-23	no assertion criteria provided	clinical testing