Submissions for variant NM_000152.5(GAA):c.1905C>A (p.Asn635Lys)

dbSNP: rs1414146587

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	RCV000780271	SCV004227901	likely pathogenic	Glycogen storage disease, type II	2023-11-21	reviewed by expert panel	curation	The NM_000152.5:c.1905C>A variant in GAA is predicted to result in the substitution of asparagine by lysine at amino acid 635 (p.Asn635Lys). The variant has been identified in four probands from Brazil, three of whom were diagnosed with infantile onset Pompe disease (IOPD), with symptoms that included hypotonia, cardiomegaly, and respiratory distress, and death in the first year of life. The fourth patient has late onset Pompe disease (LOPD). No GAA activity was available for any of these indviduals (PMID: 19588081) (PP4). Two of these patients have been reported to be compound heterozygous for the variant and another variant in GAA that has been classified as pathogenic by the ClinGen LD VCEP; c.2501_2502delCA (p.Thr834Argfs48Ter) in a patient with IOPD, and c.-32-3C>A in a patient with LOPD. The phase was not confirmed. A further two patients are homozygous for the variant (PMID: 19588081)(PM3_Strong). This variant results in 0% GAA activity in cells and 0.1% GAA activity in medium and is abnormally synthesized and processed when expressed in COS-7 or HEK293T cells, and was classified as Class B ("potentially less severe") by Kroos et al, 2012 (PMID: 22644586) (PS3_Moderate). The computational predictor REVEL gives a score of 0.61 which is neither above nor below the thresholds predicting a damaging (>0.7) or benign (<0.5) impact on GAA function. The highest population minor allele frequency in gnomAD v4.0. is 0.00002522 (1/39644 alleles) in the East Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). Another missense variant at the same amino acid position, c.1903A>G (p.Asn635Asp), has been reported in individuals with Pompe disease (PMID: 37087815, Clinical diagnostic laboratory). The evidence from c.1905C>A (p.Asn635Lys) will be used to support the classification of c.1903A>G (p.Asn635Asp) and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 632823). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PM3, PS3_Moderate, PP4, PM2_Supporting. (Classification approved by the ClinGen Lysosomal Diseases VCEP on November 21, 2023)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780271	SCV000917398	pathogenic	Glycogen storage disease, type II	2018-10-26	criteria provided, single submitter	clinical testing	Variant summary: GAA c.1905C>A (p.Asn635Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 237820 control chromosomes. c.1905C>A has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect was estimated to result in 10%-<30% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000780271	SCV001422990	likely pathogenic	Glycogen storage disease, type II	2020-01-15	criteria provided, single submitter	curation	The p.Asn635Lys variant in GAA has been reported in at least 5 individuals with glycogen storage disease II (PMID: 19588081, 22644586, 22658377) and has been identified in 0.003% (1/33926) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1414146587). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies using cells transfected with the variant provide some evidence that the p.Asn635Lys variant may impact protein function (PMID: 22644586). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been reported in the homozygous state and in combination with reported pathogenic variants in multiple individuals with glycogen storage disease II (PMID: 19588081, 22658377). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2 (Richards 2015).
Invitae	RCV000780271	SCV002212525	pathogenic	Glycogen storage disease, type II	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 635 of the GAA protein (p.Asn635Lys). 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 individuals with Pompe disease (PMID: 19588081). ClinVar contains an entry for this variant (Variation ID: 632823). 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. Experimental studies have shown that this missense change affects GAA function (PMID: 22644586). For these reasons, this variant has been classified as Pathogenic.