Submissions for variant NM_002294.3(LAMP2):c.877C>T (p.Arg293Ter)

dbSNP: rs727503118

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844639	SCV000198519	pathogenic	Danon disease; Hypertrophic cardiomyopathy	2015-04-23	criteria provided, single submitter	clinical testing	The p.Arg293X variant in LAMP2 has been reported in 4 individuals with with clin ical findings consistent with Danon disease and occured de novo in 1 of these in dividuals (Lascone 2008, Katznerg 201, Garcia-Pavia 2011). The variant was abse nt from large population studies. This nonsense variant leads to a premature ter mination codon at position 293, which is predicted to lead to a truncated or abs ent protein. Loss of function of the LAMP2 gene is known to cause Danon disease, an X-lined glycogen storage disease that includes cardiomyopathy (HCM and DCM) and skeletal myopathy (Boucek 2011). In summary, this variant meets our criteria to be classified as pathogenic for Danon disease in an X-linked dominant manner (http://www.partners.org/personalizedmedicine/LMM) based upon predicted impact to the protein, de novo occurrence, and absence from controls.
GeneDx	RCV000255646	SCV000321864	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27532257, 22695892, 18465145, 20445193, 28138913, 21896538)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000150911	SCV000636868	pathogenic	Danon disease	2022-09-24	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 163812). This premature translational stop signal has been observed in individuals with Danon disease or hypertrophic cardiomyopathy (PMID: 20960602, 21896538, 23168931). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg293*) in the LAMP2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMP2 are known to be pathogenic (PMID: 21415759).
Eurofins Ntd Llc (ga)	RCV000255646	SCV000707999	pathogenic	not provided	2017-05-02	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000255646	SCV005198630	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing