Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_000152.4(GAA):c.1841C>A (p.Thr614Lys)

CA234050

167113 (ClinVar)

Gene: GAA
Condition: glycogen storage disease II
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 92ec254b-4a9f-4cac-929c-5b6222db49b4
Approved on: 2020-04-21
Published on: 2020-05-28

HGVS expressions

NM_000152.4:c.1841C>A
NM_000152.4(GAA):c.1841C>A (p.Thr614Lys)
NC_000017.11:g.80112664C>A
CM000679.2:g.80112664C>A
NC_000017.10:g.78086463C>A
CM000679.1:g.78086463C>A
NC_000017.9:g.75701058C>A
NG_009822.1:g.16109C>A
NM_000152.3:c.1841C>A
NM_001079803.1:c.1841C>A
NM_001079804.1:c.1841C>A
NM_001079803.2:c.1841C>A
NM_001079804.2:c.1841C>A
NM_000152.5:c.1841C>A
NM_001079803.3:c.1841C>A
NM_001079804.3:c.1841C>A
ENST00000302262.7:c.1841C>A
ENST00000390015.7:c.1841C>A
ENST00000570716.1:n.281C>A
ENST00000572080.1:n.229C>A
ENST00000572803.1:n.455C>A
More

Pathogenic

Met criteria codes 5
PP4_Moderate PP3_Moderate PS3 PM2 PM3
Not Met criteria codes 1
PM5

Evidence Links 6

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Lysosomal Diseases VCEP
This variant, c.1841C>A (p.Thr614Lys), has been found in two patients published in the literature and five patients in a clinical diagnostic laboratory who have Pompe disease and residual GAA activity meeting the ClinGen LSD VCEP's specifications for PP4. These patients are compound heterozygous for the variant and either c.1076–22T>G (PMID 21484825), c.-32-13T>G (PMID 24590251, 2 laboratory patients), c.2481+102_2646+31del (one patient), c.1402A>T (p.Ile468Phe) (one patient), and unconfirmed second variant (one patient). The phase of the variants is unknown for all patients. This in trans data meets PM3. Pseudodeficiency variants are absent in the patients identified in the clinical laboratory. Therefore, PP4_Moderate can be applied. When expressed in COS cells, this variant resulted in <5% wild type activity in cells and <2% wild type activity in medium, in addition to exhibiting abnormal synthesis and processing (PMID 22644586), meeting PS3. The score for the REVEL in silico predictor, 0.835, also suggests that the variant is deleterious, meeting PP3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the European non-Finnish population, meeting PM2. There is a ClinVar entry for this variant (Variation ID: 167113, 2 star review status) with one submitter classifying the variant as pathogenic and two as likely pathogenic. In summary, this variant meets the criteria to be classified as pathogenic for Pompe disease. ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: PS3, PM2, PM3, PP3, PP4_Moderate.
Met criteria codes
PP4_Moderate
Two individuals meeting PP4 specifications have been reported in the literature including one patient with <1% normal GAA activity in cultured skin fibroblasts (PMID 21484825) and another with GAA activity below the normal range in dried blood spots (PMID 24590251). In addition, five individuals were identified in a clinical diagnostic laboratory with GAA activity below the normal range in dried blood spots; pseudodeficiency variants are absent in these cases. Therefore, PP4_Moderate can be applied.
PubMed:24590251
PP3_Moderate
REVEL (in silico meta predictor for missense changes) score = 0.835, which is higher than the LSD VCEP threshold for PP3, and therefore meets this criterion.
PS3
When expressed in COS cells, this variant resulted in <5% wild type activity in cells and <2% wild type activity in medium, in addition to exhibiting abnormal synthesis and processing. The variant was classified as functional Class B ("potentially less severe") (PMID 22644586), meeting PS3.
When expressed in COS cells, this variant resulted in <5% wild type activity in cells and <2% wild type activity in medium, in addition to exhibiting abnormal synthesis and processing. The variant was classified as functional Class B ("potentially less severe") (PMID 22644586). PubMed:22644586
PM2
The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 (European non-Finnish) which is lower than the ClinGen LSD VCEP threshold (<0.001) for PM2, meeting this criterion.
PM3
The variant was found in compound heterozygosity in two patients published in the literature who meet the specifications for PP4. In one patient, the variant is in compound heterozygosity with c.1076–22T>G, phase unknown (PMID 21484825) (in trans data will be used for classification of c.1076–22T>G and is therefore not used here in order to avoid a circular argument), and in the other patient, the variant is in compound heterozygosity with c.-32-13T>G, phase unknown (PMID 24590251) (0.5 points). In addition, in a clinical laboratory, the variant was found in two patients with c.-32-13T>G (not counted because another patient with the same genotype, phase unknown, has already been included), one patient with c.2481+102_2646+31del (0.5 points), and one patient with c.1402A>T (p.Ile468Phe) (in trans data will be used for classification of p.Ile468Phe and is therefore not used here in order to avoid a circular argument), with all patients meeting PP4_Moderate and phase unknown. This data was given a total of 1 point, meeting PM3. Additional cases have been reported but were not included because the residual GAA activity was not reported and therefore PP4 cannot be assessed (PMIDs 25544546, 27708273, 30564623).
Patient AOP13, with a prior clinical diagnosis of limb girdle muscular dystrophy, is compound heterozygous for c.1841C>A (p.Thr614Lys) and c.-32-13T>G. No individual GAA activity is provided, therefore this data will not be included. PubMed:30564623
PubMed:21484825
A patient with infantile onset Pompe disease is described who is heterozygous for three variants - c.1814C>A (p.Thr614Lys), c.1856G>A (p.Ser619Asn) (LP in ClinVar), and c.-32-13T>G. The phase is unknown. Of note, c.-32-13T>G has never been previously reported in infantile onset Pompe disease, suggesting that this variant may be in cis with one of the missense changes. GAA activity in dried blood spots was "suggestive of Pompe disease" but no specific measurements were provided; therefore this data will not be included. PubMed:25544546
Patient 1117 is compound heterozygous for c.1841C>A (p.Thr614Lys) and the known pathogenic variant, c.-32-13T>G identified by exome sequencing. The patient had a clinical diagnosis of limb girdle muscular dystrophy. PubMed:27708273
Not Met criteria codes
PM5
c.1841C>T (p.Thr614Met) (ClinVarID:286469) is classified as a variant of unknown significance in ClinVar.
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.