VCV000036477.57 - ClinVar

NM_170707.4(LMNA):c.1761G>A (p.Leu587=)

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.

(21)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_170707.4(LMNA):c.1761G>A (p.Leu587=)

Variation ID: 36477 Accession: VCV000036477.57

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 156138550 (GRCh38) [ NCBI UCSC ] 1: 156108341 (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 4, 2013	Oct 20, 2024	Jun 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_170707.4:c.1761G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_733821.1:p.Leu587=	synonymous
NM_001257374.3:c.1425G>A	NP_001244303.1:p.Leu475=	synonymous
NM_001282626.2:c.1761G>A	NP_001269555.1:p.Leu587=	synonymous
NM_001406983.1:c.1761G>A	NP_001393912.1:p.Leu587=	synonymous
NM_001406985.1:c.1761G>A	NP_001393914.1:p.Leu587=	synonymous
NM_001406986.1:c.1518G>A	NP_001393915.1:p.Leu506=	synonymous
NM_001406987.1:c.1518G>A	NP_001393916.1:p.Leu506=	synonymous
NM_001406988.1:c.1464G>A	NP_001393917.1:p.Leu488=	synonymous
NM_001406989.1:c.1425G>A	NP_001393918.1:p.Leu475=	synonymous
NM_001406990.1:c.1203G>A	NP_001393919.1:p.Leu401=	synonymous
NM_001406991.1:c.1761G>A	NP_001393920.1:p.Leu587=	synonymous
NM_001406993.1:c.1203G>A	NP_001393922.1:p.Leu401=	synonymous
NM_001406994.1:c.1137G>A	NP_001393923.1:p.Leu379=	synonymous
NM_001406995.1:c.1203G>A	NP_001393924.1:p.Leu401=	synonymous
NM_001406996.1:c.1203G>A	NP_001393925.1:p.Leu401=	synonymous
NM_001406997.1:c.1203G>A	NP_001393926.1:p.Leu401=	synonymous
NM_001406999.1:c.1137G>A	NP_001393928.1:p.Leu379=	synonymous
NM_001407000.1:c.1137G>A	NP_001393929.1:p.Leu379=	synonymous
NM_001407001.1:c.1137G>A	NP_001393930.1:p.Leu379=	synonymous
NM_170708.4:c.1671G>A	NP_733822.1:p.Leu557=	synonymous
NC_000001.11:g.156138550G>A
NC_000001.10:g.156108341G>A
NG_008692.2:g.60978G>A
LRG_254:g.60978G>A
LRG_254t1:c.*786G>A
LRG_254t2:c.1761G>A	LRG_254p2:p.Leu587=
LRG_254t3:c.1671G>A	LRG_254p3:p.Leu557=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000001.11:156138549:G:A

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

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.

0.00060 (A)

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

The Genome Aggregation Database (gnomAD), exomes 0.00190

Exome Aggregation Consortium (ExAC) 0.00208

The Genome Aggregation Database (gnomAD) 0.00210

1000 Genomes Project 0.00060

1000 Genomes Project 30x 0.00062

Trans-Omics for Precision Medicine (TOPMed) 0.00119

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00154

Links

ClinGen: CA020337 dbSNP: rs80356813 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.
LMNA		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	1845	2125

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.
Cardiomyopathy	Benign (3)	criteria provided, multiple submitters, no conflicts	Mar 8, 2018	RCV000030149.13
not specified	Benign/Likely benign (9)	criteria provided, multiple submitters, no conflicts	Oct 19, 2015	RCV000041331.34
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Oct 2, 2015	RCV000249377.11
not provided	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Jun 1, 2024	RCV000710161.34
Charcot-Marie-Tooth disease type 2	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001085192.14
Charcot-Marie-Tooth disease	Likely benign (1)	criteria provided, single submitter	-	RCV001172632.9
Primary dilated cardiomyopathy	Benign (1)	criteria provided, single submitter	Feb 5, 2024	RCV003996128.2

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 benign (Oct 19, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000114726.8 First in ClinVar: Jan 17, 2014 Last updated: May 03, 2018	Publications: PubMed (1) PubMed: 19680556 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA Number of individuals with the variant: 4 Sex: mixed
Benign (Feb 24, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Study: Canadian Open Genetics Repository Accession: SCV000901154.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019
Likely benign (Oct 02, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318704.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	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 … (more) 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)
Benign (Oct 19, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000614026.2 First in ClinVar: Aug 27, 2017 Last updated: Oct 19, 2018	Publications: PubMed (4) PubMed: 19680556‚ 19318026‚ 22570643‚ 24503780
Benign (Mar 08, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000910777.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, London Health Sciences Centre Accession: SCV001335695.1 First in ClinVar: Jun 15, 2020 Last updated: Jun 15, 2020
Likely benign (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001746873.20 First in ClinVar: Jul 10, 2021 Last updated: Oct 20, 2024	Comment: LMNA: BP4, BS2 Number of individuals with the variant: 27
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000316407.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Feb 08, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000595613.1 First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017
Benign (Sep 29, 2015)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000065024.5 First in ClinVar: May 03, 2013 Last updated: Aug 27, 2017	Comment: p.Leu587Leu in exon 11 of LMNA: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue … (more) p.Leu587Leu in exon 11 of LMNA: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.7% (36/5272) of Finnish chromosomes and 0.3% (187/59480) of European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs80356813). (less) Number of individuals with the variant: 8
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001941598.2 First in ClinVar: Sep 29, 2021 Last updated: Mar 04, 2023
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000291553.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024
Benign (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Primary dilated cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004831189.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 394
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005262263.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001917059.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (May 20, 2015)	no assertion criteria provided Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052804.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744437.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930647.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959722.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001975391.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002035596.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
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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.

Comment:

p.Leu587Leu in exon 11 of LMNA: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.7% (36/5272) of Finnish chromosomes and 0.3% (187/59480) of European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs80356813).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.	Pugh TJ	Genetics in medicine : official journal of the American College of Medical Genetics	2014	PMID: 24503780
Hallermann-Streiff Syndrome: No Evidence for a Link to Laminopathies.	Kortüm F	Molecular syndromology	2011	PMID: 22570643
Genetic variation in healthy oldest-old.	Halaschek-Wiener J	PloS one	2009	PMID: 19680556
Validation of high-resolution DNA melting analysis for mutation scanning of the LMNA gene.	Millat G	Clinical biochemistry	2009	PMID: 19318026
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA	-	-	-	-

Text-mined citations for rs80356813 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_170707.4(LMNA):c.1761G>A (p.Leu587=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80356813 ...