Submissions for variant NM_000152.5(GAA):c.2668G>C (p.Val890Leu)

gnomAD frequency: 0.00002  dbSNP: rs377286472

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000305205	SCV004809080	benign	Glycogen storage disease, type II	2023-10-01	reviewed by expert panel	curation	The NM_000152.5:c.2668G>C variant in GAA is predicted to result in the missense substitution of valine by leucine at amino acid position 890. The highest population minor allele frequency in gnomAD v2.1.1 is 0.02652 (812/30616 alleles with 13 homozygotes) in the South Asian population, which is higher than the ClinGen LSD VCEP’s threshold for BA1 (>0.01), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 255361). In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria met, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BA1. (Classified approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on October 1, 2023).
PreventionGenetics, part of Exact Sciences	RCV000245954	SCV000302683	benign	not specified		criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000245954	SCV000334977	benign	not specified	2015-09-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000305205	SCV000407303	likely benign	Glycogen storage disease, type II	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000245954	SCV000524863	benign	not specified	2016-08-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000305205	SCV000626591	benign	Glycogen storage disease, type II	2024-02-01	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852734	SCV000995449	likely benign	Hypertrophic cardiomyopathy	2017-11-14	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000305205	SCV001422936	benign	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The p.Val890Leu variant in GAA has been reported as a benign variant (by GeneDx, Invitae, EGL, and Prevention Genetics) and a VUS (by Illumina) in ClinVar (Variation ID: 255361). This variant has been identified in 2.652% (812/30616) of South Asian chromosomes, including 13 homozygotes, as well as other populations at lesser frequencies by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs377286472). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as benign for Glycogen Storage Disease II in an autosomal recessive manner based on its frequency in the general population. ACMG/AMP Criteria applied: BA1, BP4 (Richards 2015).
Genome-Nilou Lab	RCV000305205	SCV001787055	likely benign	Glycogen storage disease, type II	2021-07-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003165686	SCV003911702	likely benign	Cardiovascular phenotype	2023-01-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000305205	SCV004562842	benign	Glycogen storage disease, type II	2023-10-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000305205	SCV002094478	likely benign	Glycogen storage disease, type II	2019-10-24	no assertion criteria provided	clinical testing