Submissions for variant NM_002294.3(LAMP2):c.1075C>T (p.Gln359Ter)

dbSNP: rs1057517940

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414477	SCV000491124	likely pathogenic	not provided	2016-08-19	criteria provided, single submitter	clinical testing	The Q359X variant in the LAMP2 gene has been reported previously in a young male with a diagnosis of HCM requiring heart transplantation at 15 years of age and a history of Wolff-Parkinson-White (WPW), muscle weakness, mild developmental delay and attention deficit disorder (ADD) (Yang et al., 2005). The variant was also identified in his sister with HCM and his family history was remarkable for his mother who died at 43 years of age with a history of HCM and heart transplantation, his maternal uncle who died at 22 years of age with a history of HCM, muscular dystrophy and ADD and his maternal grandmother who died at 43 years of age with a history of HCM (Yang et al., 2005). Q359X is predicted to cause loss of normal protein function either through the loss of 52 amino acids resulting in a truncated protein product. Furthermore, cell and immunostaining studies on skeletal and myocardial biopsy samples from the proband revealed no detectable LAMP2 protein expression (Yang et al., 2005). Other nonsense variants in the LAMP2 gene have been reported in HGMD in association with Danon disease (Stenson et al., 2014). Furthermore, the Q359X pathogenic 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.In summary, Q359X in the LAMP2 gene is interpreted as a likely pathogenic variant.
Ambry Genetics	RCV002418235	SCV002717995	pathogenic	Cardiovascular phenotype	2019-04-16	criteria provided, single submitter	clinical testing	The p.Q359* pathogenic mutation (also known as c.1075C>T), located in coding exon 8 of the LAMP2 gene, results from a C to T substitution at nucleotide position 1075. This changes the amino acid from a glutamine to a stop codon within coding exon 8. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of LAMP2, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 50 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. However, this mutation has been reported in a proband with early onset hypertrophic cardiomyopathy (HCM), arrhythmia, muscle weakness, mild developmental delay, attention deficit disorder, significant family history, and absence of LAMP2 protein on cardiomyocyte and skeletal muscle biopsies (Yang Z et al. Circulation, 2005 Sep;112:1612-7). In addition, a downstream mutation, p.Q361Sfs*15, has been reported in a family with Danon disease (Taylor MR et al. J. Hum. Genet., 2007;52:830-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005090665	SCV005841073	pathogenic	Danon disease	2024-10-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln359*) in the LAMP2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acid(s) of the LAMP2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Danon disease (PMID: 16144992, 19057086). ClinVar contains an entry for this variant (Variation ID: 372712). This variant disrupts a region of the LAMP2 protein in which other variant(s) (p.Lys361Serfs*19) have been determined to be pathogenic (PMID: 17899313). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.