ClinVar Miner

Submissions for variant NM_000152.5(GAA):c.736del (p.Leu246fs) (rs886043920)

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Total submissions: 4
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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 RCV000410911 SCV001371727 likely pathogenic Glycogen storage disease, type II 2020-02-05 reviewed by expert panel curation This variant, c.736delC (p.Leu246Phefs) creates a frameshift which is predicted to cause a premature termination codon and nonsense mediated decay, resulting in no gene product. Therefore, PVS1 can be applied. The variant is absent in gnomAD v2.1.1, meeting PM2. It was found in a patient with limb-girdle muscular dystrophy and a second GAA variant, c.546G>A (PMID 30564623); however, because the residual GAA activity level was not reported, PP4 cannot be assessed, and PM3 was not applied. There is a ClinVar entry for this variant (Variation ID: 288505; 2 star review status) with two submitters classifying the variant as pathogenic and one as likely pathogenic. 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: PVS1, PM2.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000726173 SCV000701280 pathogenic not provided 2016-06-06 criteria provided, single submitter clinical testing
Invitae RCV000410911 SCV000752054 pathogenic Glycogen storage disease, type II 2017-11-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu246Phefs*22) in the GAA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with GAA-related disease. ClinVar contains an entry for this variant (Variation ID: 288505). Loss-of-function variants in GAA are known to be pathogenic (PMID: 18425781). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000410911 SCV000486042 likely pathogenic Glycogen storage disease, type II 2016-03-18 no assertion criteria provided clinical testing

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