Variant: NM_000152.5(GAA):c.796C>T (p.Pro266Ser)

CA401363495

556117 (ClinVar)

Gene: GAA

Condition: glycogen storage disease II

Inheritance Mode: Autosomal recessive inheritance

UUID: 2b5077ea-d72a-4564-a83c-2aea98c3b4a8

HGVS expressions

NM_000152.5:c.796C>T
NM_000152.5(GAA):c.796C>T (p.Pro266Ser)
NC_000017.11:g.80107660C>T
CM000679.2:g.80107660C>T
NC_000017.10:g.78081459C>T
CM000679.1:g.78081459C>T
NC_000017.9:g.75696054C>T
NG_009822.1:g.11105C>T
ENST00000302262.8:c.796C>T
ENST00000302262.7:c.796C>T
ENST00000390015.7:c.796C>T
ENST00000570803.5:c.796C>T
NM_000152.3:c.796C>T
NM_001079803.1:c.796C>T
NM_001079804.1:c.796C>T
NM_000152.4:c.796C>T
NM_001079803.2:c.796C>T
NM_001079804.2:c.796C>T
NM_001079803.3:c.796C>T
NM_001079804.3:c.796C>T

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: PM2_Supporting PS3_Supporting PP4_Moderate PM3_Strong BP4

• Not Met criteria codes: PS1 PP3 PM5

Expert Panel

Lysosomal Diseases VCEP

Criteria Specification Information

Criteria Specification: ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Evidence submitted by expert panel

Lysosomal Diseases VCEP

The NM_000152.5:c.796C>T variant in GAA is a missense variant predicted to cause substitution of proline by serine at amino acid 266 (p.Pro266Ser). At least seven patients with this variant and features consistent with Pompe disease have been reported. This includes 2 patients with documented laboratory values showing deficient GAA activity (<10% normal or below reference range in leukocytes) (PMID: 17092519, 29124014) (PP4_Moderate). These patients are all compound heterozygous for the variant and another variant in GAA classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP, phase unknown, including c.1309C>T (p.Arg437Cys) (PMID: 25526786), c.1316T>A (p.Met439Lys) (PMID: 17092519, 31193175,), c.1935C>A (p.Asp645Glu) (PMID: 28394184) (ClinVar# SCV002032138.1), c.546G>T (PMID: 29124014) (ClinVar# SCV002032139.1), and c.1602_1605delinsAGG (p.Asn535GlyfsTer43) (PMID: 28394184) (PM3_Strong). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant resulted in 14-18% wild type GAA activity, in two different studies, when expressed in COS cells. (PMID: 18425781, 19862843). Western blot revealed presence of the active 76kDa GAA band, but at a much lower level than wild type (PMID: 19862843). Additional variants at this amino acid positions have been reported (c.797C>T (p.Pro266Leu); c.796C>A (p.Pro266Thr) (PMID: 29451150); these variants have not been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP. The score from the in silico metapredictor REVEL is 0.476 (BP4), which is a single piece of conflicting evidence in comparison with the evidence for pathogenicity. There is a ClinVar entry for this variant (Variation ID:556117, 2 star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. In summary, based on the overall evidence, 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 (Specifications Version 2): PM3_Strong, PP4_Moderate, PS3_Supporting, PM2_Supporting, BP4.

Met criteria codes

• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PS3_Supporting: This variant resulted in 14-18% wild type GAA activity, in two different studies, when expressed in COS cells. (PMID: 18425781, 19862843). Western blot revealed presence of the active 76kDa GAA band, but at a much lower level than wild type (PMID: 19862843).
• PP4_Moderate: At least seven patients with this variant and features consistent with Pompe disease have been reported. This includes 2 patients with documented values showing deficient GAA activity (<10% normal or below reference range in leukocytes) (PMID: 17092519, 29124014), sufficient to meet the ClinGen LSD VCEP’s specifications for PP4_Moderate.
• PM3_Strong: Seven patients with features consistent with Pompe disease are compound heterozygous for the variant and a variant in GAA classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP, phase unknown, including c.1309C>T (p.Arg437Cys) (PMID: 25526786; 0.5 points), c.1316T>A (p.Met439Lys) (PMID: 17092519, 31193175, 2 x 0.5 points), c.1935C>A (p.Asp645Glu) (PMID: 28394184) (ClinVar# SCV002032138.1) (0.5 points), c.546G>T (PMID: 29124014) (ClinVar# SCV002032139.1) (2 x 0.5 points), and c.1602_1605delinsAGG (p.Asn535GlyfsTer43) (PMID: 28394184) (0.25 points). Total 3.25 points (PM3_Strong).
• BP4: REVEL score = 0.476 which is lower than the LSD VCEP threshold for BP4 (<0.5), and therefore meets this criterion.

Not Met criteria codes

• PS1: The p.Pro266Ser amino acid change has not been reported with another nucleotide change in ClinVar, HGMD Pro, LOVD or pompevariantdatabase.nl.
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: A missense change (p.Pro266Leu, c.797C>T) at the same amino acid residue has been reported by ClinVar. Another missense change (p.Pro266Thr, c.796C>A) at the same amino acid residue is reported in literature. These variants have not been classified as pathogenic or likely pathogenic by the ClinGen LSD VCEP. Therefore, PM5 is not met.

Approved on: 2022-06-30

Published on: 2022-06-30