VCV000044434.48 - ClinVar

NM_002294.3(LAMP2):c.661G>A (p.Gly221Arg)

Germline

Classification

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

Conflicting classifications of pathogenicity
Uncertain significance (1); Benign (7); Likely benign (5)

13 out of 19 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.661G>A (p.Gly221Arg)

Variation ID: 44434 Accession: VCV000044434.48

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq24 X: 120447921 (GRCh38) [ NCBI UCSC ] X: 119581776 (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 9, 2018	Feb 15, 2026	Jan 28, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_002294.3:c.661G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002285.1:p.Gly221Arg	missense
NM_001122606.1:c.661G>A	NP_001116078.1:p.Gly221Arg	missense
NM_013995.2:c.661G>A	NP_054701.1:p.Gly221Arg	missense
NC_000023.11:g.120447921C>T
NC_000023.10:g.119581776C>T
NG_007995.1:g.26429G>A
LRG_749:g.26429G>A
LRG_749t1:c.661G>A	LRG_749p1:p.Gly221Arg
LRG_749t2:c.661G>A	LRG_749p2:p.Gly221Arg
LRG_749t3:c.661G>A	LRG_749p3:p.Gly221Arg

... more HGVS ... less HGVS

Protein change

G221R

Other names

p.G221R:GGA>AGA

Canonical SPDI

NC_000023.11:120447920:C:T

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.

0.00159 (T)

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

Exome Aggregation Consortium (ExAC) 0.00130

The Genome Aggregation Database (gnomAD), exomes 0.00155

1000 Genomes Project 0.00159

1000 Genomes Project 30x 0.00166

The Genome Aggregation Database (gnomAD) 0.00187

The Genome Aggregation Database (gnomAD) 0.00193

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00199

Trans-Omics for Precision Medicine (TOPMed) 0.00214

The Genome Aggregation Database (gnomAD), exomes 0.00226

Links

ClinGen: CA134161 dbSNP: rs145169006 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 specified	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Oct 9, 2025	RCV000037424.20
Danon disease	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Jan 28, 2026	RCV000465775.24
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Jun 15, 2017	RCV000617835.4
not provided	Likely benign (4)	criteria provided, single submitter	Sep 24, 2020	RCV000755557.16
Cardiomyopathy	Benign (2)	criteria provided, multiple submitters, no conflicts	Feb 21, 2023	RCV000853049.3
Intellectual disability	Uncertain significance (1)	criteria provided, single submitter	Apr 7, 2020	RCV001089470.5

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.
Benign (Jun 27, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Danon disease	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604090.6 First in ClinVar: Mar 08, 2017 Last updated: Jan 24, 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

Benign (Oct 09, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Not specified	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV007319686.1 First in ClinVar: Jan 17, 2026 Last updated: Jan 17, 2026	Publications: PubMed (3) PubMed: 23785128‚ 27600940‚ 28074886 Comment: show BS1, BS2 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 13

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: SCV000560067.11 First in ClinVar: Apr 17, 2017 Last updated: Feb 15, 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

Likely benign (May 26, 2015) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061081.5 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Comment: show p.Gly221Arg in LAMP2: This variant is not expected to have clinical significance because it has been identified in 0.2% (84/47999) of European chromosomes, incl uding 30 males, by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org/; dbSNP rs145169006). (less) 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: 14

Benign (Mar 04, 2019) 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: SCV001362570.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (3) PubMed: 23785128‚ 27600940‚ 28771489 Comment: show Variant summary: LAMP2 c.661G>A (p.Gly221Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 200310 control chromosomes in the gnomAD database, including 1 homozygote and 95 hemizygotes. The observed variant frequency is approximately 120 fold of the estimated maximal expected allele frequency for a pathogenic variant in LAMP2 causing Cardiomyopathy phenotype (1.3e-05), strongly suggesting that the variant is benign. The variant c.661G>A has been reported in the literature in patients with dilated (DCM) or hypertrophic (HCM) cardiomyopathies, however without evidence for causality (e.g. Mook 2013, Cecconi 2016, Mademont-Soler 2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (2x)/likely benign(4x). Based on the evidence outlined above, the variant was classified as 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

Likely benign (Sep 24, 2020) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000207890.6 First in ClinVar: Feb 24, 2015 Last updated: Apr 09, 2018	Comment: show This variant is associated with the following publications: (PMID: 25091525, 23785128, 28074886, 27600940) (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

Benign (Feb 21, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004240711.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	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 (Oct 31, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000740589.1 First in ClinVar: Apr 14, 2018 Last updated: Apr 14, 2018	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 (May 28, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Danon disease	Mendelics Accession: SCV001142004.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Benign (Apr 28, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Danon disease	Illumina Laboratory Services, Illumina Accession: SCV001330759.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 23785128‚ 25091525 Comment: show This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as 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

Benign (Jun 15, 2017) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV000736900.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Comment: show This alteration is classified as 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

Benign (May 14, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995807.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Uncertain significance (Apr 07, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Intellectual disability (X-linked dominant inheritance)	Human Genetics Laboratory, State University of Rio de Janeiro Accession: SCV000996528.4 First in ClinVar: May 04, 2020 Last updated: Aug 03, 2025	Observation: 1 Collection method: research Allele origin: inherited Affected status: yes more Observation 1 Collection method: research Allele origin: inherited Affected status: yes Zygosity: 1 Single Heterozygote Sex: female Ethnicity/Population group: mixed Geographic origin: Brazil Comment on evidence: "variation affecting protein" was previously submitted as the functional consequence for NM_001122606.1:c.661G>A, but without providing the result of a functional assay.

Likely benign (-) 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: SCV001926689.1 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

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798138.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 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

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Study: VKGL Data-share Consensus Accession: SCV001955388.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Clinical Genetics, Academic Medical Center Study: VKGL Data-share Consensus Accession: SCV001925136.1 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

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV001964692.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 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

Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided	Danon disease	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734734.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	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:

p.Gly221Arg in LAMP2: This variant is not expected to have clinical significance because it has been identified in 0.2% (84/47999) of European chromosomes, incl uding 30 males, by the Exome Aggregation Consortium (ExAC, http://exac.broadins titute.org/; dbSNP rs145169006).

Comment:

Variant summary: LAMP2 c.661G>A (p.Gly221Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 200310 control chromosomes in the gnomAD database, including 1 homozygote and 95 hemizygotes. The observed variant frequency is approximately 120 fold of the estimated maximal expected allele frequency for a pathogenic variant in LAMP2 causing Cardiomyopathy phenotype (1.3e-05), strongly suggesting that the variant is benign. The variant c.661G>A has been reported in the literature in patients with dilated (DCM) or hypertrophic (HCM) cardiomyopathies, however without evidence for causality (e.g. Mook 2013, Cecconi 2016, Mademont-Soler 2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (2x)/likely benign(4x). Based on the evidence outlined above, the variant was classified as benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Comment:

This alteration is classified as 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
Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.	Mademont-Soler I	PloS one	2017	PMID: 28771489
Post-mortem whole-exome analysis in a large sudden infant death syndrome cohort with a focus on cardiovascular and metabolic genetic diseases.	Neubauer J	European journal of human genetics : EJHG	2017	PMID: 28074886
Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy.	Cecconi M	International journal of molecular medicine	2016	PMID: 27600940
Dominant muscular dystrophy with a novel SYNE1 gene mutation.	Fanin M	Muscle & nerve	2015	PMID: 25091525
Targeted sequence capture and GS-FLX Titanium sequencing of 23 hypertrophic and dilated cardiomyopathy genes: implementation into diagnostics.	Mook OR	Journal of medical genetics	2013	PMID: 23785128

Text-mined citations for rs145169006 ...

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