ClinVar Miner

Submissions for variant NM_002294.3(LAMP2):c.929-1G>A (rs727504262)

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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 RCV000154245 SCV000203900 likely pathogenic Danon disease 2013-02-11 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786340 SCV000925117 likely pathogenic not provided 2016-10-04 no assertion criteria provided provider interpretation The patient provided a lab report for a relative with Danon disease. The test included sequencing of 10 genes associated with HCM: ACTC, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PRKAG2, TNNI3, TNNT2, TPM1. A variant was found: hemizygous c.929-1G>A (formerly known as IVS7-1G>A) in intron 7 of the LAMP2 gene. c.929-1G>A (formerly known as IVS7-1G>A) in the LAMP2 gene (NM_002294.2) Given that this variant has been reported in another family with Danon disease, that the variant disturbs a canonical splice site and that it is absent from controls, we also consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant was found in two siblings from Germany with Danon disease (Horvath et al 2003). The proband had Danon disease that was diagnosed at 25 years of age after heart failure due to hypertrophic cardiomyopathy. A pacemaker was placed. He developed generalized muscle weakness, eventually requiring a wheelchair. He later had a heart transplant. The proband's sister also experienced heart failure and had the variant. The variant was not present in 100 healthy controls. The nucleotide at position 929-1 is completely conserved across species. This variant disturbs a canonical splice site within the LAMP2 gene. Incorrect splicing predicts a loss of 55 amino acids from the LAMP-2 protein (Horvath et al 2003). Variants in the LAMP2 gene causing Danon disease are almost always truncating, frameshift or disturb splice sites. At least twenty-six patients with Danon disease are reported in the literature with variants in LAMP2 that disturb splice sites (Arad et al 2005, Boucek et al 2011, Horvath et al 2003 Maron et al 2009, Nishino et al 2000, Sugie et al 2002, Yang et al 2005). The variant was not present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 2016). Coverage at this site is 60x.

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