VCV000409223.12 - ClinVar

NM_002294.3(LAMP2):c.778C>T (p.His260Tyr)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance (1); Likely benign (2)

3 out of 3 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002294.3(LAMP2):c.778C>T (p.His260Tyr)

Variation ID: 409223 Accession: VCV000409223.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq24 X: 120446391 (GRCh38) [ NCBI UCSC ] X: 119580246 (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	Apr 17, 2017	Mar 7, 2026	Jan 28, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_002294.3:c.778C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002285.1:p.His260Tyr	missense
NM_001122606.1:c.778C>T	NP_001116078.1:p.His260Tyr	missense
NM_013995.2:c.778C>T	NP_054701.1:p.His260Tyr	missense
NC_000023.11:g.120446391G>A
NC_000023.10:g.119580246G>A
NG_007995.1:g.27959C>T
LRG_749:g.27959C>T
LRG_749t1:c.778C>T	LRG_749p1:p.His260Tyr
LRG_749t2:c.778C>T	LRG_749p2:p.His260Tyr
LRG_749t3:c.778C>T	LRG_749p3:p.His260Tyr

... more HGVS ... less HGVS

Protein change

H260Y

Other names

Canonical SPDI

NC_000023.11:120446390:G:A

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.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00004

Links

ClinGen: CA10505252 dbSNP: rs778577575 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	955	1133

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	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Jan 28, 2026	RCV000462750.11
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Jan 8, 2025	RCV002411475.3

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.	Expand all rows Collapse all rows 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.
Uncertain significance (Jun 11, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Danon disease (X-linked dominant inheritance)	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Accession: SCV002769047.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 28771489‚ 30108015‚ 30847666 Comment: show Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0110 - This gene is known to be associated with X-linked dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a histidine to a tyrosine (exon 6). (N) 0253 - Variant is hemizygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (3 heterozygotes, 2 hemizygotes, 0 homozygotes). (P) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0600 - Variant is located in an annotated domain or motif (Lysosome-associated membrane glycoprotein; PDB, NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. The variant has been previously reported as pathogenic in patients with HCM (PMID: 30108015), and also reported as a VUS in patients with HCM and arrhythmia (ClinVar, PMID: 28771489, 30847666). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely benign (Jan 08, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002673273.3 First in ClinVar: Nov 29, 2022 Last updated: Apr 28, 2025	Publications: PubMed (3) PubMed: 28255936‚ 28771489‚ 30108015 Comment: show This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Jan 28, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Danon disease	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000549127.8 First in ClinVar: Apr 17, 2017 Last updated: Mar 07, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0110 - This gene is known to be associated with X-linked dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a histidine to a tyrosine (exon 6). (N) 0253 - Variant is hemizygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (3 heterozygotes, 2 hemizygotes, 0 homozygotes). (P) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0600 - Variant is located in an annotated domain or motif (Lysosome-associated membrane glycoprotein; PDB, NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. The variant has been previously reported as pathogenic in patients with HCM (PMID: 30108015), and also reported as a VUS in patients with HCM and arrhythmia (ClinVar, PMID: 28771489, 30847666). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance.	van Lint FHM	Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation	2019	PMID: 30847666
Clinical Findings and Prognosis of Danon Disease. An Analysis of the Spanish Multicenter Danon Registry.	López-Sainz Á	Revista espanola de cardiologia (English ed.)	2019	PMID: 30108015
Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.	Mademont-Soler I	PloS one	2017	PMID: 28771489
Sudden Arrhythmic Death During Exercise: A Post-Mortem Genetic Analysis.	Campuzano O	Sports medicine (Auckland, N.Z.)	2017	PMID: 28255936

Text-mined citations for rs778577575 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026