NM_000152.5:c.2040G>A

CA502179100

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 79cd37cc-4450-4d1c-a569-1b774f68b80e

HGVS expressions

NM_000152.5:c.2040G>A
NC_000017.11:g.80113027G>A
CM000679.2:g.80113027G>A
NC_000017.10:g.78086826G>A
CM000679.1:g.78086826G>A
NC_000017.9:g.75701421G>A
NG_009822.1:g.16472G>A
NM_000152.3:c.2040G>A
NM_001079803.1:c.2040G>A
NM_001079804.1:c.2040G>A
NM_000152.4:c.2040G>A
NM_001079803.2:c.2040G>A
NM_001079804.2:c.2040G>A
NM_001079803.3:c.2040G>A
NM_001079804.3:c.2040G>A
ENST00000302262.7:c.2040G>A
ENST00000390015.7:c.2040G>A
ENST00000570716.1:n.480G>A
ENST00000572080.1:n.459G>A

Likely Pathogenic

• Met criteria codes: PS3_Supporting PM3_Supporting PP3 PP4 PM2

• Not Met criteria codes: BP7

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Evidence submitted by expert panel

Lysosomal Diseases VCEP

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.

Met criteria codes

• PS3_Supporting: This variant, c.2040G>A, alters the last nucleotide of exon 14. While the amino acid is unchanged (p.Leu680=), the variant was investigated for an impact on splicing. Sequence analysis of cDNA from a patient who is compound heterozygous for the variant and a missense change in GAA showed that intron 14 was included in some of the transcripts. Inclusion of intron 14 is predicted to result in a frameshift (p.Leu680Leufs35Ter) (PMID 17723315). However, quantitative methods were not used in the amplification process, and therefore the proportion of transcripts containing intron 14 is unknown. In addition, amplification of the second allele in cDNA from the patient prevented assessment of whether the c.2040G>A variant completely abolishes normal splicing or not.
• PM3_Supporting: This variant was found in compound heterozygosity with a pathogenic variant in GAA, c.1927G>A (p.Gly643Arg), in a patient who with Pompe disease who meets the ClinGen LSD VCEP's PP4 specifications (PMID 17723315, 23430500). The phase is unknown. 0.5 points meeting PM3_Supporting.
• PP3: This variant, c.2040G>A, does not alter an amino acid (p.Leu680=) but alters the last nucleotide of exon 14. The results from in silico splice spite prediction programs suggest that this variant impacts normal splicing. There is a 18.18% reduction in score for Human Splicing Finder and a 104.88% reduction in score for MaxEntScan. In addition, Human Splicing Finder predicts the creation of a new acceptor site downstream from the broken donor site (increase in score 60.46%). This meets the LSD VCEP’s specifications for PP3 (>2% decrease in score for Human Splicing Finder and >15% decrease in score for MaxEntScan).
• PP4: A patient has been been reported with this variant and GAA activity <10% normal (PMID 17723315). This meets the criteria for PP4.
• PM2: This variant is not in gnomAD v2.1.1.

Not Met criteria codes

• BP7: This variant, c.2040G>A, does not alter the amino acid (p.Leu680=). However, cDNA studies from a patient with the variant and in silico predictors indicate that the variant impacts splicing. Therefore, BP7 is not met.

Approved on: 2020-06-16

Published on: 2020-11-11