Submissions for variant NM_000152.5(GAA):c.1979G>A (p.Arg660His)

gnomAD frequency: 0.00009  dbSNP: rs374143224

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000169600	SCV002540655	pathogenic	Glycogen storage disease, type II	2022-03-01	reviewed by expert panel	curation	The NM_000152.5: c.1979G>A variant in GAA is a missense variant predicted to cause substitution of arginine by histidine at amino acid 660 (p.Arg660His). More than nine individuals with features consistent with Pompe disease have been reported with this variant. Of these patients 3 probands (and two siblings) have documented laboratory values indicating GAA deficiency in the affected range in dried blood spot, or muscle, or <1% activity in cultured skin fibroblasts (PMID: 21484825, 25037089, 27649523), and three probands are reported to have low GAA activity and to be on enzyme replacement therapy (PP4_Moderate). Six patients are compound heterozygous for the variant and a variant classified as pathogenic by the ClinGen LSD VCEP. For two patients, the second variant was confirmed in trans by parental testing - c.525delT (PMID: 30559630, possibly same case in PMID: 30214072), and c.670C>T (p.Arg224Trp) (PMID: 14643388) – and in four patients the phase of the second variant is unconfirmed - c.655G>A (p.Gly219Arg) (PMID: 29122469), c.1082C>T (p.Pro361Leu) (PMID: 21484825), c.1998C>T (p.Arg600Cys) (PMID: 14643388), and c.2560C>T (p.Arg854Ter) (PMID: 30214072). Two homozygous siblings have also been reported (PMID: 27649523) (PM3_Very Strong). Two probands have been reported who are compound heterozygous for the variant and either c.-32-17_-32-10del8ins30 (PMID: 25037089; two affected siblings), or c.1114C>T (p.His372Tyr) (PMID: 30214072). The allelic data from these patients will be used in the classification of the second variant and is not included here to avoid circular logic. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00025 (6/23566) in the African population, which is lower than the ClinGen LSD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). In two independent studies, in which the variant was expressed in COS cells, the GAA activity was <2% wild type, indicating that the variant has a damaging effect on GAA function (PS3_Supporting). The computational predictor REVEL gives a score of 0.976 which is above the threshold of 0.7, evidence that correlates with impact to GAA function (PP3). Another variant, c.1978C>T (p.Arg660Cys), has been reported at this position. p.Arg660His will be used to support the classification of p.Arg660Cys and thus PM5 is not applied here, in order to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 189172; 2 star review status) with nine submitters classifying the variant as pathogenic, and three as likely pathogenic. In summary, this variant meets the criteria to be classified as Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen LSD VCEP (Specifications Version 2.0): PM3_VeryStrong, PP4_Moderate, PP3, PS3_Supporting, PM2_Supporting. (Approved by LSD VCEP on Feb 15, 2022).
Counsyl	RCV000169600	SCV000221116	likely pathogenic	Glycogen storage disease, type II	2015-02-04	criteria provided, single submitter	literature only
GeneDx	RCV000256037	SCV000322397	pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 14643388); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31086307, 31127727, 30559630, 33073007, 29122469, 14643388, 22555271, 22658377, 19862843, 22521436, 21484825, 26402642, 30281819, 20472203, 20638881, 34852371, 22253258, 19343043, 27649523)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169600	SCV000626537	pathogenic	Glycogen storage disease, type II	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 660 of the GAA protein (p.Arg660His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) and/or Pompe disease (PMID: 14643388, 20472203, 20638881, 21484825, 22521436, 22555271, 27649523). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189172). 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%. Experimental studies have shown that this missense change affects GAA function (PMID: 14643388). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000256037	SCV000706386	pathogenic	not provided	2017-02-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000169600	SCV000894163	pathogenic	Glycogen storage disease, type II	2021-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169600	SCV000917390	pathogenic	Glycogen storage disease, type II	2018-03-09	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1979G>A (p.Arg660His) 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 0.00013 in 31000 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.00013 vs 0.0042), allowing no conclusion about variant significance. c.1979G>A has been reported in the literature in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease)(Pipo_2003, Bernstein_2010, Bali_2011). These data indicate that the variant is likely to be associated with disease. At least two publications reports experimental evidence evaluating an impact on enzyme activity (Pipo_2003, Bali_2011). The most pronounced variant effect results in <10% of normal activity. Three 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000256037	SCV001245692	pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000256037	SCV002021201	pathogenic	not provided	2023-07-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169600	SCV004195416	pathogenic	Glycogen storage disease, type II	2024-03-03	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000169600	SCV001133216	likely pathogenic	Glycogen storage disease, type II	2019-09-26	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000169600	SCV001459744	pathogenic	Glycogen storage disease, type II	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000256037	SCV001956452	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000256037	SCV001966553	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895169	SCV004709697	pathogenic	GAA-related disorder	2024-01-03	no assertion criteria provided	clinical testing	The GAA c.1979G>A variant is predicted to result in the amino acid substitution p.Arg660His. This variant was reported in the homozygous and compound heterozygous states in multiple patients with Pompe disease (Nazari et al. 2017. PubMed ID: 27649523, Pipo et al. 2003. PubMed ID: 14643388, Kindel et al. 2012. PubMed ID: 22555271). In at least two patients carrying this variant, biochemical testing indicated GAA deficiency (Nazari et al. 2017. PubMed ID: 27649523). This variant is reported in 0.025% of alleles in individuals of African descent in gnomAD. This variant was classified as pathogenic by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel and most laboratories in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/189172/). This variant is interpreted as pathogenic.