ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.2040G>A (p.Leu680=)

dbSNP: rs2039280842
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel RCV001265222 SCV001443297 likely pathogenic Glycogen storage disease, type II 2020-06-16 reviewed by expert panel curation This variant, c.2040G>A, does not result in an amino acid change (p.Leu680=) but alters the last nucleotide of exon 14. This variant is not present in gnomAD v2.1.1, meeting PM2. This variant was found in compound heterozygosity with a pathogenic missense variant, c.1927G>A (p.Gly643Arg), in GAA in a patient who also meets the ClinGen LSD VCEP's PP4 specifications (PMID 17723315, 23430500). The phase is unknown. This data meets PM3_Supporting. The results from in silico splice spite prediction programs, Human Splicing Finder and MaxEntScan, suggest that this variant breaks the normal donor splice site. In addition, Human Splicing Finder predicts the creation of a new acceptor site downstream from the broken donor site. This meets the ClinGen LSD VCEP's specifications for PP3. Furthermore, sequence analysis of cDNA from a patient who is compound heterozygous for the variant and p.Gly643Arg in GAA showed that intron 14 was included in some of the transcripts (PMID 17723315). Inclusion of intron 14 is predicted to result in a frameshift (p.Leu680Leufs35Ter). However, quantitative methods were not used in the amplification process, and therefore the proportion of transcripts containing intron 14 is unknown. This data meets the specifications for PS3_Supporting. There is no ClinVar entry for this variant. 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: PS3_Supporting, PM2, PM3_Supporting, PP3, PP4.
Revvity Omics, Revvity RCV003135906 SCV003828581 likely pathogenic not provided 2022-07-01 criteria provided, single submitter clinical testing

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