Submissions for variant NM_002294.3(LAMP2):c.864+3_864+6del

dbSNP: rs397516751

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157986	SCV000207921	pathogenic	not provided	2016-06-30	criteria provided, single submitter	clinical testing	c.864+3_6delGAGT: IVS6+3_6delGAGT in intron 6 of the LAMP2 gene (NM_002294.2). Using capital letters to denote exonic sequence and lower case letters to denote intronic sequence, the normal sequence with the bases that are deleted in braces is: TGgt{gagt}aaca.The c.864+3_6delGAGT variant in the LAMP2 gene has been reported in association with Danon disease (Arad M et al., 2005; Bui Y et al., 2008). Arad et al. reported c.864+3_6delGAGT (reported as IVS6+1_4delGTGA due to alternate nomenclature) in two brothers with severe cardiomyopathy, and Bui et al. identified this variant in a 16 year old male with early onset cardiomyopathy and Danon disease. This variant destroys the splice donor site in intron 6 and is predicted to cause abnormal gene splicing. Other splice site variants in the LAMP2 gene have been reported in association with Danon disease. In summary, c.864+3_6delGAGT in the LAMP2 gene is interpreted as a pathogenic variant. The variant is found in DCM,HCM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000037432	SCV000815693	pathogenic	Danon disease	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 6 of the LAMP2 gene. It does not directly change the encoded amino acid sequence of the LAMP2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Danon's disease (PMID: 15673802, 18282207, 25458169; Invitae). This variant is also known as IVS6+1_4delGTGA. ClinVar contains an entry for this variant (Variation ID: 44442). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000157986	SCV001447722	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371830	SCV002687798	pathogenic	Cardiovascular phenotype	2018-08-14	criteria provided, single submitter	clinical testing	The c.864+3_864+6delGAGT intronic pathogenic mutation is located 3 nucleotides after coding exon 6 in the LAMP2 gene. This mutation results from a deletion of 4 nucleotides at positions c864+3 to c.864+66. This mutation, also reported as IVS6+1_4delGTGA, has been reported in multiple individuals with Danon disease (Arad M et al. N. Engl. J. Med., 2005 Jan;352:362-72; Bui YK et al. Pediatr Transplant, 2008 Mar;12:246-50; Hashida Y et al. J Cardiol, 2015 Aug;66:168-74). This mutation alters the splice donor site and is predicted to remove 41 amino acids from the protein (Arad M et al. N. Engl. J. Med., 2005 Jan;352:362-72). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844640	SCV000061089	likely pathogenic	Hypertrophic cardiomyopathy	2007-03-26	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000037432	SCV004808338	pathogenic	Danon disease	2023-03-22	no assertion criteria provided	clinical testing