rs397516751

Variant names:

• chrX-120446298-TACTC-T
• rs397516751
• NM_002294.3:c.864+3_864+6delGAGT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_002294.3(LAMP2):​c.864+3_864+6delGAGT variant causes a splice region, 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: LAMP2 NM_002294.3 splice_region, intron
• Clinical Significance: Pathogenic/Likely 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

Our verdict: Pathogenic. The variant received 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 [Likely_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 rank	MANE	Protein	UniProt
LAMP2	NM_002294.3	c.864+3_864+6delGAGT		splice_region_variant, intron_variant	Intron 6 of 8	ENST00000200639.9	NP_002285.1
LAMP2	NM_001122606.1	c.864+3_864+6delGAGT		splice_region_variant, intron_variant	Intron 6 of 8		NP_001116078.1
LAMP2	NM_013995.2	c.864+3_864+6delGAGT		splice_region_variant, intron_variant	Intron 6 of 8		NP_054701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LAMP2	ENST00000200639.9	c.864+3_864+6delGAGT		splice_region_variant, intron_variant	Intron 6 of 8	1	NM_002294.3	ENSP00000200639.4

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/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Danon disease Pathogenic:2

Mar 22, 2023

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

not provided Pathogenic:2

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18282207, 15673802, 34714385, 25458169) -

Hypertrophic cardiomyopathy Pathogenic:1

Mar 26, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1

Aug 14, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=0/100	disease causing (ClinVar)

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; COSMIC: COSV52355287;