VCV000044438.14 - ClinVar

NM_002294.3(LAMP2):c.824A>G (p.Asn275Ser)

Germline

Classification

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

Uncertain significance
Uncertain significance (4)

4 out of 5 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.824A>G (p.Asn275Ser)

Variation ID: 44438 Accession: VCV000044438.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq24 X: 120446345 (GRCh38) [ NCBI UCSC ] X: 119580200 (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	Jan 31, 2015	May 3, 2026	Feb 24, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_002294.3:c.824A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002285.1:p.Asn275Ser	missense
NM_001122606.1:c.824A>G	NP_001116078.1:p.Asn275Ser	missense
NM_013995.2:c.824A>G	NP_054701.1:p.Asn275Ser	missense
NC_000023.11:g.120446345T>C
NC_000023.10:g.119580200T>C
NG_007995.1:g.28005A>G
LRG_749:g.28005A>G
LRG_749t1:c.824A>G	LRG_749p1:p.Asn275Ser
LRG_749t2:c.824A>G	LRG_749p2:p.Asn275Ser
LRG_749t3:c.824A>G	LRG_749p3:p.Asn275Ser

... more HGVS ... less HGVS

Protein change

N275S

Other names

Canonical SPDI

NC_000023.11:120446344:T:C

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.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00004

The Genome Aggregation Database (gnomAD) 0.00006

The Genome Aggregation Database (gnomAD) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00000

Links

ClinGen: CA134183 dbSNP: rs397516747 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	1135

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 specified	Uncertain significance (2)	criteria provided, single submitter	Feb 24, 2026	RCV000037428.7
Danon disease	Uncertain significance (1)	criteria provided, single submitter	Aug 28, 2024	RCV000685066.7
not provided	Uncertain significance (1)	criteria provided, single submitter	Jul 31, 2024	RCV002222366.3
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Aug 8, 2022	RCV004018837.1

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 (Aug 08, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV004894677.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: show The c.824A>G (p.N275S) alteration is located in exon 6 (coding exon 6) of the LAMP2 gene. This alteration results from a A to G substitution at nucleotide position 824, causing the asparagine (N) at amino acid position 275 to be replaced by a serine (S). Based on insufficient or conflicting evidence, 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 (Jul 31, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV002499813.3 First in ClinVar: Apr 23, 2022 Last updated: Sep 29, 2024	Comment: show Observed in patients with HCM referred for genetic testing at GeneDx and in the published literature; however, one individual harbored additional pathogenic variants in other genes associated with cardiomyopathy (PMID: 27532257); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257) (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 (Aug 28, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Danon disease	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000812538.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 25, 2025	Publications: PubMed (2) PubMed: 27532257‚ 28492532 Comment: show This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 275 of the LAMP2 protein (p.Asn275Ser). This variant is present in population databases (rs397516747, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 44438). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LAMP2 protein function with a negative predictive value of 80%. 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 (Feb 24, 2026) 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: SCV004241070.2 First in ClinVar: Feb 04, 2024 Last updated: May 03, 2026	Publications: PubMed (1) PubMed: 27532257 Comment: show Variant summary: LAMP2 c.824A>G (p.Asn275Ser) results in a conservative amino acid change located in the Lysosome-associated membrane glycoprotein 2-like, luminal domains (IPR048528) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. The variant allele was found at a frequency of 9.1e-06 in 1203555 control chromosomes including 5 hemizygotes suggesting a benign role. c.824A>G has been reported in the literature in individuals affected with Cardiomyopathy (Walsh_2017). These report(s) do 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 have been ascertained in the context of this evaluation (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 44438). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (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 04, 2009) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061085.4 First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 1

Comment:

The c.824A>G (p.N275S) alteration is located in exon 6 (coding exon 6) of the LAMP2 gene. This alteration results from a A to G substitution at nucleotide position 824, causing the asparagine (N) at amino acid position 275 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

Observed in patients with HCM referred for genetic testing at GeneDx and in the published literature; however, one individual harbored additional pathogenic variants in other genes associated with cardiomyopathy (PMID: 27532257); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257)

Comment:

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 275 of the LAMP2 protein (p.Asn275Ser). This variant is present in population databases (rs397516747, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 44438). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LAMP2 protein function with a negative predictive value of 80%. 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:

Variant summary: LAMP2 c.824A>G (p.Asn275Ser) results in a conservative amino acid change located in the Lysosome-associated membrane glycoprotein 2-like, luminal domains (IPR048528) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. The variant allele was found at a frequency of 9.1e-06 in 1203555 control chromosomes including 5 hemizygotes suggesting a benign role. c.824A>G has been reported in the literature in individuals affected with Cardiomyopathy (Walsh_2017). These report(s) do 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 have been ascertained in the context of this evaluation (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 44438). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257

Text-mined citations for rs397516747 ...

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 May 09, 2026