VCV000180868.20 - ClinVar

NM_002294.3(LAMP2):c.73C>T (p.Arg25Trp)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance
Uncertain significance (5)

5 out of 7 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.73C>T (p.Arg25Trp)

Variation ID: 180868 Accession: VCV000180868.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq24 X: 120456761 (GRCh38) [ NCBI UCSC ] X: 119590616 (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	Feb 24, 2015	Feb 15, 2026	Jan 27, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_002294.3:c.73C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002285.1:p.Arg25Trp	missense
NM_001122606.1:c.73C>T	NP_001116078.1:p.Arg25Trp	missense
NM_013995.2:c.73C>T	NP_054701.1:p.Arg25Trp	missense
NC_000023.11:g.120456761G>A
NC_000023.10:g.119590616G>A
NG_007995.1:g.17589C>T
LRG_749:g.17589C>T
LRG_749t1:c.73C>T	LRG_749p1:p.Arg25Trp
LRG_749t2:c.73C>T	LRG_749p2:p.Arg25Trp
LRG_749t3:c.73C>T	LRG_749p3:p.Arg25Trp

... more HGVS ... less HGVS

Protein change

R25W

Other names

p.R25W:CGG>TGG

Canonical SPDI

NC_000023.11:120456760: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.

0.00026 (A)

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

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00003

The Genome Aggregation Database (gnomAD) 0.00013

Trans-Omics for Precision Medicine (TOPMed) 0.00014

The Genome Aggregation Database (gnomAD) 0.00015

1000 Genomes Project 0.00026

1000 Genomes Project 30x 0.00042

Links

ClinGen: CA333632 dbSNP: rs730880478 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.
not provided	Uncertain significance (3)	criteria provided, single submitter	May 15, 2023	RCV000157960.5
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Apr 4, 2025	RCV000621632.4
Danon disease	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 27, 2026	RCV000707593.11
not specified	Uncertain significance (1)	criteria provided, single submitter	Jan 12, 2024	RCV003987379.1

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.	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 (Apr 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV000736261.6 First in ClinVar: Apr 14, 2018 Last updated: Jul 13, 2025	Publications: PubMed (1) PubMed: 29915097 Comment: show The p.R25W variant (also known as c.73C>T), located in coding exon 2 of the LAMP2 gene, results from a C to T substitution at nucleotide position 73. The arginine at codon 25 is replaced by tryptophan, an amino acid with dissimilar properties. Based on data from gnomAD, the T allele has an overall frequency of 0.003% (6/190735) total alleles studied, with 3 hemizygotes observed. The highest observed frequency was 0.02% (4/18373) of African/African American alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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

Uncertain significance (Jan 27, 2026) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Danon disease	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000836694.9 First in ClinVar: Oct 10, 2018 Last updated: Feb 15, 2026	Publications: PubMed (2) PubMed: 28492532‚ 29915097 Comment: show This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 25 of the LAMP2 protein (p.Arg25Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with sudden unexplained death (PMID: 29915097). ClinVar contains an entry for this variant (Variation ID: 180868). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (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

Uncertain significance (May 15, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000207895.11 First in ClinVar: Feb 24, 2015 Last updated: Jun 10, 2023	Comment: show Identified in a patient with sudden unexplained death and negative autopsy findings in the published literature (Shanks et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29915097) (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

Uncertain significance (Jan 12, 2024) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004803261.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Publications: PubMed (1) PubMed: 29915097 Comment: show Variant summary: LAMP2 c.73C>T (p.Arg25Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 169128 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.73C>T has been reported in the literature in an individual affected with sudden unexplained death (Shanks_2018). This report does not provide unequivocal conclusions about association of the variant with Danon Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29915097). ClinVar contains an entry for this variant (Variation ID: 180868). Based on the evidence outlined above, the variant was classified as uncertain significance. (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

Uncertain significance (Jul 08, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Danon disease	Fulgent Genetics, Fulgent Genetics Accession: SCV002814258.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Clinical Genetics, Academic Medical Center Study: VKGL Data-share Consensus Accession: SCV001919578.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV001928923.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

The p.R25W variant (also known as c.73C>T), located in coding exon 2 of the LAMP2 gene, results from a C to T substitution at nucleotide position 73. The arginine at codon 25 is replaced by tryptophan, an amino acid with dissimilar properties. Based on data from gnomAD, the T allele has an overall frequency of 0.003% (6/190735) total alleles studied, with 3 hemizygotes observed. The highest observed frequency was 0.02% (4/18373) of African/African American alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 25 of the LAMP2 protein (p.Arg25Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with sudden unexplained death (PMID: 29915097). ClinVar contains an entry for this variant (Variation ID: 180868). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Identified in a patient with sudden unexplained death and negative autopsy findings in the published literature (Shanks et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29915097)

Comment:

Variant summary: LAMP2 c.73C>T (p.Arg25Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3e-05 in 169128 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.73C>T has been reported in the literature in an individual affected with sudden unexplained death (Shanks_2018). This report does not provide unequivocal conclusions about association of the variant with Danon Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29915097). ClinVar contains an entry for this variant (Variation ID: 180868). Based on the evidence outlined above, the variant was classified as uncertain significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Importance of Variant Interpretation in Whole-Exome Molecular Autopsy: Population-Based Case Series.	Shanks GW	Circulation	2018	PMID: 29915097

Text-mined citations for rs730880478 ...

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