Submissions for variant NM_000152.5(GAA):c.710C>T (p.Ala237Val)

dbSNP: rs121907944

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000664615	SCV002817450	uncertain significance	Glycogen storage disease, type II	2022-11-02	reviewed by expert panel	curation	The NM_000152.5:c.710C>T variant in GAA is a missense variant that is predicted to result in the substitution of alanine by valine at amino acid 237 (p.Ala237Val). A patient with late onset Pompe disease and this variant has been described with a severely reduced GAA activity (<10% normal) and an increase of total glycogen in muscle (PMID: 15668445, 17573812, 17643989) (PP4_Moderate). This patient is compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LSD VCEP, c.877G>A (p.Gly293Arg) (PMID: 15668445, 17573812, 17643989) (PM3_Supporting). Another patient has been reported who is compound heterozygous for the variant and p.Met173del (PMID: 28196920). However, the cDNA changes for these variants were not provided and therefore the data was not included. The highest population minor allele frequency in gnomAD v2.1.1. is 0.00013 (4/30616 alleles) in the South Asian population which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). When expressed in COS cells, this variant had "greater than 2% wild-type GAA activity", but the activity was not provided (PS3 not met). The computational predictor REVEL gives a score of 0.693 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function (neither PP3 nor BP4 is met). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease. GAA-specific ACMG-AMP criteria met, as specified by the ClinGen LSD VCEP (Specifications Version 2.0): PP4_Moderate, PM2_Supporting, PM3_Supporting. (Classification approved by the ClinGen LSD VCEP on November 2, 2022)
Counsyl	RCV000664615	SCV000788610	uncertain significance	Glycogen storage disease, type II	2017-04-28	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000664615	SCV001422612	uncertain significance	Glycogen storage disease, type II	2020-01-22	criteria provided, single submitter	curation	The heterozygous p.Ala237Val variant in GAA has been reported in 1 German individual with Glycogen Storage Disease II (PMID: 15668445), and has also been reported as a VUS by Counsyl and pathogenic by OMIM in ClinVar (Variation ID: 4035). This variant has been identified in 0.013% (4/30616) of South Asian chromosomes and 0.001% (1/113342) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121907944). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in combination with a reported pathogenic variant and in an individual with Glycogen Storage Disease II increases the likelihood that the p.Ala237Val variant is pathogenic (PMID: 15668445). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3_Supporting, PM2, PP4 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000664615	SCV002265225	likely pathogenic	Glycogen storage disease, type II	2024-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 237 of the GAA protein (p.Ala237Val). This variant is present in population databases (rs121907944, gnomAD 0.01%). This missense change has been observed in individual(s) with Pompe disease (PMID: 15668445). ClinVar contains an entry for this variant (Variation ID: 4035). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAA protein function. Experimental studies have shown that this missense change affects GAA function (PMID: 19862843). This variant disrupts the p.A237G amino acid residue in GAA. Other variant(s) that disrupt this residue have been observed in individuals with GAA-related conditions (PMID: 31086307), which suggests that this may be a clinically significant amino acid residue. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265547	SCV002547862	uncertain significance	not specified	2022-05-05	criteria provided, single submitter	clinical testing	Variant summary: GAA c.710C>T (p.Ala237Val) results in a non-conservative amino acid change located in the Galactose mutarotase, N-terminal barrel domain (IPR031727) of 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 2e-05 in 250946 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.710C>T has been reported in the literature as a compound heterozygous genotype in at-least one individual affected by late-onset Pompe disease who has been subsequently cited by others (example, Anneser_2005, Muller-Felber_2007, Schoser_2007). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV003329226	SCV004036873	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17027861, 15668445, 17643989, 34426522, 19343043, 22253258, 17573812, 30275481, 19862843)
Baylor Genetics	RCV000664615	SCV005058751	uncertain significance	Glycogen storage disease, type II	2024-01-30	criteria provided, single submitter	clinical testing
OMIM	RCV000004250	SCV000024416	pathogenic	GLYCOGEN STORAGE DISEASE II, ADULT FORM	2005-01-25	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004751198	SCV005358151	uncertain significance	GAA-related disorder	2024-09-03	no assertion criteria provided	clinical testing	The GAA c.710C>T variant is predicted to result in the amino acid substitution p.Ala237Val. This variant has been reported in the compound heterozygous state with the GAA c.877G>A (p.Gly293Arg) variant in an individual with late onset Pompe disease (Anneser et al. 2005. PubMed ID: 15668445; Schoser et al. 2007. PubMed ID: 17573812; Müller-Felber et al. 2007. PubMed ID: 17643989). Functional studies have shown that this variant impacts GAA protein function (Flanagan et al. 2009. PubMed ID: 19862843). Of note, another variant impacting this same amino acid [c.710C>G (p.Ala237Gly)] has been reported in an individual with glycogen storage disease 2 (Supplemental Table S3, Kishnani et al. 2019. PubMed ID: 31086307). The c.710C>T variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD and is reported as a variant of uncertain significance by the ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/4035/) At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.