rs397516751

Positions:

• chrX-120446298-TACTC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_002294.3(LAMP2):​c.864+3_864+6del variant causes a splice donor 5th base, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: LAMP2 NM_002294.3 splice_donor_5th_base, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.39

Genes affected

LAMP2 (HGNC:6501): (lysosomal associated membrane protein 2) The protein encoded by this gene is a member of a family of membrane glycoproteins. This glycoprotein provides selectins with carbohydrate ligands. It may play a role in tumor cell metastasis. It may also function in the protection, maintenance, and adhesion of the lysosome. Alternative splicing of this gene results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-120446298-TACTC-T is Pathogenic according to our data. Variant chrX-120446298-TACTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 44442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120446298-TACTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.864+3_864+6del		splice_donor_5th_base_variant, intron_variant		ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.864+3_864+6del		splice_donor_5th_base_variant, intron_variant			NP_001116078.1
LAMP2	NM_013995.2	c.864+3_864+6del		splice_donor_5th_base_variant, intron_variant			NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.864+3_864+6del		splice_donor_5th_base_variant, intron_variant		1	NM_002294.3	ENSP00000200639	P3

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Danon disease Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Mar 22, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2016	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 26, 2007

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516751; hg19: chrX-119580153;