Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000844641 | SCV000198532 | pathogenic | Hypertrophic cardiomyopathy | 2020-09-30 | criteria provided, single submitter | clinical testing | The c.183+1G>A variant in LAMP2 has been reported in at least 4 individuals with clinical features of Danon disease, including a reportedly de novo occurrence (Boucek 2011 PMID: 21415759, Alfares 2015 PMID: 25611685; Walsh 2017 PMID: 27532257; LMM internal data; Invitae pers. comm.). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 163816) and was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the LAMP2 gene is an established disease mechanism in X-linked Danon disease. In summary, this variant meets criteria to be classified as pathogenic for X-linked Danon disease. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PM6, PS4_Moderate. |
| Labcorp Genetics |
RCV000150913 | SCV000549124 | pathogenic | Danon disease | 2023-04-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 163816). Disruption of this splice site has been observed in individuals with Danon disease and hypertrophic cardiomyopathy (PMID: 21415759, 27532257; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the LAMP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LAMP2 are known to be pathogenic (PMID: 21415759). |
| Ambry Genetics | RCV003343655 | SCV004050920 | likely pathogenic | Cardiovascular phenotype | 2023-06-27 | criteria provided, single submitter | clinical testing | The c.183+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 2 of the LAMP2 gene. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The stop codon in the predicted resulting transcript occurs in the 5' end ofthe LAMP2 gene. As such, this alteration may escape nonsense-mediated mRNAdecay and/or be prone to rescue by reinitiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). The exact functional effect of this alteration is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant has been previously reported in a cohort of patients reported to have Danon disease, and in a hypertrophic cardiomyopathy cohort (Boucek D et al. Genet Med, 2011 Jun;13:563-8; Walsh R et al. Genet Med, 2017 Feb;19:192-203). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |