VCV003251932.1 - ClinVar

NM_002294.3(LAMP2):c.864+5G>A

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002294.3(LAMP2):c.864+5G>A

Variation ID: 3251932 Accession: VCV003251932.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq24 X: 120446300 (GRCh38) [ NCBI UCSC ] X: 119580155 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 15, 2024	Jul 15, 2024	Dec 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002294.3:c.864+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001122606.1:c.864+5G>A		intron variant
NM_013995.2:c.864+5G>A		intron variant
NC_000023.11:g.120446300C>T
NC_000023.10:g.119580155C>T
NG_007995.1:g.28050G>A
LRG_749:g.28050G>A
LRG_749t2:c.864+5G>A
LRG_749t3:c.864+5G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000023.11:120446299:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

sequence_variant_affecting_splicing; Sequence Ontology [ SO:1000071]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LAMP2		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	716	888

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Danon disease	Likely pathogenic (1)	criteria provided, single submitter	Dec 1, 2023	RCV004586376.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Dec 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing, research	Danon disease (X-linked inheritance) Affected status: yes Allele origin: unknown, germline	Department of Cardiovascular Medicine, The University of Tokyo, Graduate School of Medicine Accession: SCV005077699.1 First in ClinVar: Jul 15, 2024 Last updated: Jul 15, 2024	Publications: PubMed (10) PubMed: 38246647‚ 37277924‚ 24691104‚ 21161685‚ 23262972‚ 29463847‚ 28822614‚ 9536098‚ 10972294‚ 34459252 DOI: 10.1016/j.genrep.2019.100564 DOI: 10.1016/j.genrep.2019.100564 Comment: A case report (PMID:38246647) showed the exon 6 skipping in LAMP2 gene with human tissues and demonstrated LAMP2 deficiency in cardiac and skeletal muscle. Exon … (more) A case report (PMID:38246647) showed the exon 6 skipping in LAMP2 gene with human tissues and demonstrated LAMP2 deficiency in cardiac and skeletal muscle. Exon 6 skipping in LAMP2 gene is a many reported cause of Danon disease in human (PMID:37277924, PMID:24691104, PMID:21161685, PMID: 23262972, PMID:29463847, PMID:28822614, PMID: 9536098, PMID:10972294, DOI:10.1016/j.genrep.2019.100564), and it was also confirmed in mice model (PMID: 34459252). This variant was confirmed to cause exon 6 skipping (PS3). This variant is absent in databases, including ExAC, gnomAD Global AF, gnomAD EAS AF, TMM 54K JPN AF (PM2 Supporting). This variant cause exon 6 skipping resulting in protein length changing (PM4), and the patient's phenotype was highly specific for Danon disease (PP4). (less) Observation 1: Clinical Features: cardiomyopathy (present) , muscle weakness (present) , mental retardation (present) Indication for testing: heart failure Family history: no Age: 30-39 years Sex: male Ethnicity/Population group: Asian Geographic origin: Japan Tissue: blood Segregation observed: no Secondary finding: no Observation 2: Tissue: patient's cardiac tissue Method: RT-PCR and Sanger sequencing Result: exon 6 skipping Observation 3: Tissue: patient's cardiac tissue and skeletal muscle Method: Immunihistochemistry using monoclonal antibodies to LAMP2 Result: decreased LAMP2

Comment:

A case report (PMID:38246647) showed the exon 6 skipping in LAMP2 gene with human tissues and demonstrated LAMP2 deficiency in cardiac and skeletal muscle. Exon 6 skipping in LAMP2 gene is a many reported cause of Danon disease in human (PMID:37277924, PMID:24691104, PMID:21161685, PMID: 23262972, PMID:29463847, PMID:28822614, PMID: 9536098, PMID:10972294, DOI:10.1016/j.genrep.2019.100564), and it was also confirmed in mice model (PMID: 34459252). This variant was confirmed to cause exon 6 skipping (PS3). This variant is absent in databases, including ExAC, gnomAD Global AF, gnomAD EAS AF, TMM 54K JPN AF (PM2 Supporting). This variant cause exon 6 skipping resulting in protein length changing (PM4), and the patient's phenotype was highly specific for Danon disease (PP4).

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
sequence_variant_affecting_splicing (SO:1000071)	RT-PCR and Sanger sequencing Method citation(s): PubMed(1) Immunihistochemistry using monoclonal antibodies to LAMP2 Method citation(s): PubMed(1)	exon 6 skipping decreased LAMP2	Department of Cardiovascular Medicine, The University of Tokyo, Graduate School of Medicine Accession: SCV005077699.1	Publications PubMed (10) DOI: 10.1016/j.genrep.2019.100564

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A Pathogenic LAMP2 Non-Canonical Splice Site Mutation Caused Danon Disease Requiring Heart Transplantation.	Abe R	Circulation journal : official journal of the Japanese Circulation Society	2024	PMID: 38246647
Identification of a novel splicing-altering LAMP2 variant in a Chinese family with Danon disease.	Fu D	ESC heart failure	2023	PMID: 37277924
LAMP2 Cardiomyopathy: Consequences of Impaired Autophagy in the Heart.	Alcalai R	Journal of the American Heart Association	2021	PMID: 34459252
Small-Vessel Vasculopathy Due to Aberrant Autophagy in LAMP-2 Deficiency.	Nguyen HT	Scientific reports	2018	PMID: 29463847
Heterogeneity in a large pedigree with Danon disease: Implications for pathogenesis and management.	Roos JCP	Molecular genetics and metabolism	2018	PMID: 28822614
Novel LAMP2 mutations in Chinese patients with Danon disease cause varying degrees of clinical severity.	Luo SS	Clinical neuropathology	2014	PMID: 24691104
Lysosomal storage and advanced senescence in the brain of LAMP-2-deficient Danon disease.	Furuta A	Acta neuropathologica	2013	PMID: 23262972
Danon disease: intrafamilial phenotypic variability related to a novel LAMP-2 mutation.	Cottinet SL	Journal of inherited metabolic disease	2011	PMID: 21161685
Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease).	Nishino I	Nature	2000	PMID: 10972294
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098
-	-	-	-	DOI: 10.1016/j.genrep.2019.100564
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Record last updated Jul 23, 2024

ClinVar Genomic variation as it relates to human health

NM_002294.3(LAMP2):c.864+5G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...