rs143347747
Variant summary
Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2_SupportingPM3_SupportingPP4_ModerateBP4
This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2395C>T variant in GAA is a missense variant predicted to cause substitution of His by Tyr at amino acid 799 (p.His799Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00038 (6/15954 alleles) in the African population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.443 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). It only has been reported in one case as LOPD, in which has unknown phase concurrence in compound heterozygous with c.-32-13T>G (PMID:22958975). Thus met PM3_supporting. The LOPD case has been reported to have GAA residue level 0.25 (normal cutoff unknown. But average of 20 LOPD patients is 8.35, so <10% of normal mean control level). Thus PP4_moderate is applied. There is a ClinVar entry for this variant (Variation ID: 284886, 2 star review status) with 8 submitters classifying the variant as Uncertain significance with no conflicts. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP4_moderate, PM3_supporting, BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP, September 5, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815726/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
Publications
- glycogen storage disease IIInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
- glycogen storage disease due to acid maltase deficiency, infantile onsetInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- glycogen storage disease due to acid maltase deficiency, late-onsetInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000184 AC: 28AN: 152206Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000362 AC: 9AN: 248542 AF XY: 0.0000222 show subpopulations
GnomAD4 exome AF: 0.00000959 AC: 14AN: 1460582Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5AN XY: 726604 show subpopulations
GnomAD4 genome 0.000184 AC: 28AN: 152324Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6AN XY: 74474 show subpopulations
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Uncertain:7
This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 799 of the GAA protein (p.His799Tyr). This variant is present in population databases (rs143347747, gnomAD 0.03%). This missense change has been observed in individual(s) with Pompe disease (PMID: 22958975). ClinVar contains an entry for this variant (Variation ID: 284886). 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 not expected to disrupt GAA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
The NM_000152.5:c.2395C>T variant in GAA is a missense variant predicted to cause substitution of His by Tyr at amino acid 799 (p.His799Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00038 (6/15954 alleles) in the African population, which is lower than the ClinGen LD VCEP’s threshold for PM2_Supporting (<0.001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.443 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function (BP4). It only has been reported in one case as LOPD, in which has unknown phase concurrence in compound heterozygous with c.-32-13T>G (PMID: 22958975). Thus met PM3_supporting. The LOPD case has been reported to have GAA residue level 0.25 (normal cutoff unknown. But average of 20 LOPD patients is 8.35, so <10% of normal mean control level). Thus PP4_moderate is applied. There is a ClinVar entry for this variant (Variation ID: 284886, 2 star review status) with 8 submitters classifying the variant as Uncertain significance with no conflicts. In summary, this variant meets the criteria to be classified as Uncertain significance for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): PM2_supporting, PP4_moderate, PM3_supporting, BP4. (Classification approved by the ClinGen Lysosomal Diseases VCEP, September 5, 2023) -
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The p.His799Tyr variant in GAA has not been previously reported in individuals with Glycogen Storage Disease II but has been identified in 0.038% (6/15954) of African chromosomes, 0.006% (2/34532) of Latino chromosomes, and 0.005% (1/18354) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs143347747). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported as a VUS by EGL Genetic Diagnostics and Invitae in ClinVar (Variation ID: 284886). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The Histidine (His) at position 799 is not highly conserved in mammals and evolutionary distant species, and 5 species (nile tilapia, princess of Burundi, burton's mouthbreather, zebra mbuna, pundamilia nyererei) carry a Tyrosine (Tyr), raising the possibility that this change at this position may be tolerated. In summary, the clinical significance of the p.His799Tyr variant is uncertain. ACMG/AMP Criteria applied: PM2, BP4 (Richards 2015). -
not provided Uncertain:2
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not specified Uncertain:1
Variant summary: GAA c.2395C>T (p.His799Tyr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 150978 control chromosomes, predominantly within the Latino and African subpopulations at a frequency of 0.00092 and 0.00031, respectively, in the gnomAD database (v3.1 genomes dataset). These frequencies are not significantly higher than the estimated maximum expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (0.0042), allowing no conclusion about variant significance. The variant, c.2395C>T, has been reported in the literature in a compound heterozygote individual affected with the late form of Glycogen Storage Disease Type 2 (Pompe Disease) (Musumeci_2012), however, in a later report this patient was noted to carry two co-occurring (potentially) pathogenic variants, which could explain the phenotype, although the phase of the three variants was not specified (Montagnese_2015). These reports do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Cardiovascular phenotype Uncertain:1
The p.H799Y variant (also known as c.2395C>T), located in coding exon 16 of the GAA gene, results from a C to T substitution at nucleotide position 2395. The histidine at codon 799 is replaced by tyrosine, an amino acid with similar properties. This variant has been detected in an individual with late onset Pompe disease; however, this individual also had two additional variants in the GAA gene (phase unknown) (Musumeci O et al. Mol Genet Metab, 2012 Nov;107:480-4; Montagnese F et al. J Neurol, 2015 Feb;262:968-78). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at