ClinVar Miner

Submissions for variant NM_002294.3(LAMP2):c.1093+1G>A (rs727504742)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156041 SCV000205754 pathogenic Danon disease 2013-08-29 criteria provided, single submitter clinical testing The 1093+1G>A variant in LAMP2 has not been previously reported in individuals w ith cardiomyopathy or Danon disease, or been observed in large population studie s. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or a bsent protein (loss of function). Two other variants at this splice site (1093+1 G>C and 1093+2T>A) have been reported in individuals with Danon disease and were shown to alter splicing (DiBlasi 2008, Tu?on 2008). Loss of function variants i n LAMP2 are associated with Danon disease, an X-linked 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 (http ://pcpgm.partners.org/LMM) based on the predicted impact of the variant.
GeneDx RCV000522279 SCV000618104 pathogenic not provided 2016-05-10 criteria provided, single submitter clinical testing Although the c.1093+1 G>A variant has not been published as a pathogenic variant or as a benign variant to our knowledge, it is classified in ClinVar as a pathogenic variant in association with Danon disease (ClinVar SCV000205754.2; Landrum et al., 2016). Furthermore, it destroys the canonical splice donor site in intron 8 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants in the LAMP2 gene, including two other variants at the same splice site, have been reported in HGMD in association with Danon disease (Stenson et al., 2014). Furthermore, the c.1093+1 G>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations

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