ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.1064T>C (p.Leu355Pro) (rs766074609)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel, ClinGen RCV000353485 SCV001371747 pathogenic Glycogen storage disease, type II 2020-05-03 reviewed by expert panel curation This variant, c.1064T>C (p.Leu355Pro), has been found in at least 6 individuals with Pompe disease and deficient GAA activity meeting the ClinGen LSD VCEP's specifications for PP4. Of those individuals, three are homozygous for the variant (PMIDs 14972326, 17723315, 24016645). One individual is compound heterozygous for the variant and a pathogenic missense variant, c.670C>T (p.Arg224Trp), with the variants confirmed in trans (PMID 23632174). Another two individuals are compound heterozygous for the variant and a unique missense variant; either c.1106T >C (p.Leu369Pro), phase unknown (PMID 23430493), or c.380G>T (p.Cys127Phe), confirmed in trans (PMID 24016645). The in trans data from these two patients will be used in the assessment of those variants and was not included here in order to avoid a circular argument. PM3_Strong is met. Additional cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 could not be assessed (PMIDs 16917947, 17573812, 17643989, 18429042, 23787031, 30023291) or the nomenclature of the in trans variant was not consistent (PMID 30595407). When expressed in COS cells, this variant results in absent GAA activity, and there is evidence of abnormal synthesis and processing of GAA on Western blot (PMIDs 14695532, 14972326, 19862843). The deleterious impact of this variant is also supported by the in silico meta-predictor, REVEL (score = 0.805), meeting PP3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00003 in the Latino population, meeting PM2. There is a ClinVar entry for this variant (Variation ID: 284093, 2 star review status) with two submitters each classifying the variant as pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3_Strong, PP3, PP4.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725389 SCV000336568 pathogenic not provided 2015-10-29 criteria provided, single submitter clinical testing
Counsyl RCV000353485 SCV000486373 pathogenic Glycogen storage disease, type II 2016-05-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000353485 SCV001363615 pathogenic Glycogen storage disease, type II 2019-02-21 criteria provided, single submitter clinical testing Variant summary: GAA c.1064T>C (p.Leu355Pro) 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 8.1e-06 in 245966 control chromosomes (gnomAD). c.1064T>C has been reported in the literature in multiple compound heterozygote and homozygote individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) (e.g. Hermans 2004, Pittis 2008, Nino 2012). One of these publications also reported experimental evidence evaluating an impact on protein function, and found the complete absence of enzyme activity and lack protein product in transiently transfected COS cells (Hermans 2004). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Institute Rare Disease Group,Broad Institute RCV000353485 SCV001423067 pathogenic Glycogen storage disease, type II 2020-01-22 no assertion criteria provided curation The p.Leu355Pro variant in GAA has been reported in 23 individuals (including 4 Italian, 4 Portuguese, 2 Israeli, 2 Columbian, 1 German, 1 Turkish, and 1 Syrian individuals) with Glycogen Storage Disease II, segregated with disease in 2 affected siblings from 1 family (PMID: 16917947, 14972326, 18429042, 17643989, 14695532, 17723315, 23632174, 23430493, 23787031, 24016645, 30023291, 17213836, 17573812, 30595407), and has also been reported pathogenic by Counsyl and EGL in ClinVar (Variation ID: 284093). This variant has been identified in 0.003% (1/34580) of Latino chromosomes and 0.001% (1/113290) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs766074609). 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 with COS cells transfected with this variant provide some evidence that the p.Leu355Pro variant may impact GAA processing and activity (PMID: 14695532, 14972326). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The Leucine (Leu) at position 355 is not conserved in one mammal species and more evolutionary distant species, slightly raising the possibility that a change at this position may be tolerated. The presence of this variant in the homozygous state and in combination with pathogenic and likely variants, and in individuals with Glycogen Storage Disease II increases the likelihood that the p.Leu355Pro variant is pathogenic (PMID: 23430493, 24016645, 23632174, 17723315, 14972326). The phenotype of individuals homozygous and heterozygous for this variant is highly specific for Glycogen Storage Disease II based on reduced GAA activity in relevant tissues, consistent with disease (PMID: 23430493, 24016645, 23632174, 17723315, 14972326). In summary, this variant meets criteria to be classified as pathogenic for Glycogen Storage Disease II in an autosomal recessive manner based on in vitro functional studies with COS cells transfected with this variant and multiple occurrences with pathogenic or likely pathogenic variants in individuals with Glycogen Storage Disease II. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2, PP3, PP4 (Richards 2015).

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