VCV000066916.18 - ClinVar

NM_170707.4(LMNA):c.618C>G (p.Phe206Leu)

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.

(6)

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.

Pathogenic/Likely pathogenic

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.618C>G (p.Phe206Leu)

Variation ID: 66916 Accession: VCV000066916.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 156134507 (GRCh38) [ NCBI UCSC ] 1: 156104298 (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	Oct 20, 2013	May 1, 2024	Sep 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_170707.4:c.618C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_733821.1:p.Phe206Leu	missense
NM_005572.4:c.618C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005563.1:p.Phe206Leu	missense
NM_001257374.3:c.282C>G	NP_001244303.1:p.Phe94Leu	missense
NM_001282624.2:c.375C>G	NP_001269553.1:p.Phe125Leu	missense
NM_001282625.2:c.618C>G	NP_001269554.1:p.Phe206Leu	missense
NM_001282626.2:c.618C>G	NP_001269555.1:p.Phe206Leu	missense
NM_170708.4:c.618C>G	NP_733822.1:p.Phe206Leu	missense
NC_000001.11:g.156134507C>G
NC_000001.10:g.156104298C>G
NG_008692.2:g.56935C>G
LRG_254:g.56935C>G
LRG_254t2:c.618C>G
	P02545:p.Phe206Leu

... more HGVS ... less HGVS

Protein change

F206L, F125L, F94L

Other names

p.F206L:TTC>TTG

Canonical SPDI

NC_000001.11:156134506:C:G

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.

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

Links

ClinGen: CA018318 UniProtKB: P02545#VAR_064964 dbSNP: rs267607629 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.
not provided	Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 7, 2023	RCV000057431.16
Charcot-Marie-Tooth disease type 2	Pathogenic (1)	criteria provided, single submitter	Sep 12, 2023	RCV000694277.8
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Dec 2, 2021	RCV002354249.2

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 pathogenic (May 24, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000234676.14 First in ClinVar: Jul 05, 2015 Last updated: Jun 17, 2023	Comment: Reported in one individual diagnosed with generalized skeletal muscle involvement and cardiac conduction disease at the age of 57 (Scharner et al., 2011); Not observed … (more) Reported in one individual diagnosed with generalized skeletal muscle involvement and cardiac conduction disease at the age of 57 (Scharner et al., 2011); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10939567, 26659599, 20848652, 35242549, 34862408) (less)
Likely pathogenic (Sep 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003816982.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Dec 02, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002657350.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 20848652‚ 26659599‚ 28663758 Comment: The p.F206L pathogenic mutation (also known as c.618C>G), located in coding exon 3 of the LMNA gene, results from a C to G substitution at … (more) The p.F206L pathogenic mutation (also known as c.618C>G), located in coding exon 3 of the LMNA gene, results from a C to G substitution at nucleotide position 618. The phenylalanine at codon 206 is replaced by leucine, an amino acid with highly similar properties. This variant has been detected in multiple individuals affected with laminopathy phenotypes, including limb-girdle muscular dystrophy (LGMD), dilated cardiomyopathy (DCM), and/or arrhythmias, and co-segregation has been reported in at least three families (Scharner J et al. Hum. Mutat., 2011 Feb;32:152-67; GeneDx pers comm; Invitae pers. comm.). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Sep 12, 2023)	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: SCV000822713.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 28492532‚ 20848652 Comment: This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 206 of the LMNA protein (p.Phe206Leu). … (more) This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 206 of the LMNA protein (p.Phe206Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant LMNA-related conditions (PMID: 20848652; Invitae). ClinVar contains an entry for this variant (Variation ID: 66916). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function. For these reasons, this variant has been classified as Pathogenic. (less)
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Epithelial Biology; Institute of Medical Biology, Singapore Accession: SCV000088545.1 First in ClinVar: Oct 20, 2013 Last updated: Oct 20, 2013
Uncertain significance (Dec 22, 2016)	Flagged submission flagged submission (EGL Classification Definitions 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000703083.2 First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018	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: 1 Sex: mixed
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

Reported in one individual diagnosed with generalized skeletal muscle involvement and cardiac conduction disease at the age of 57 (Scharner et al., 2011); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10939567, 26659599, 20848652, 35242549, 34862408)

Comment:

The p.F206L pathogenic mutation (also known as c.618C>G), located in coding exon 3 of the LMNA gene, results from a C to G substitution at nucleotide position 618. The phenylalanine at codon 206 is replaced by leucine, an amino acid with highly similar properties. This variant has been detected in multiple individuals affected with laminopathy phenotypes, including limb-girdle muscular dystrophy (LGMD), dilated cardiomyopathy (DCM), and/or arrhythmias, and co-segregation has been reported in at least three families (Scharner J et al. Hum. Mutat., 2011 Feb;32:152-67; GeneDx pers comm; Invitae pers. comm.). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 206 of the LMNA protein (p.Phe206Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant LMNA-related conditions (PMID: 20848652; Invitae). ClinVar contains an entry for this variant (Variation ID: 66916). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function. For these reasons, this variant has been classified as Pathogenic.

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
LMNA Sequences of 60,706 Unrelated Individuals Reveal 132 Novel Missense Variants in A-Type Lamins and Suggest a Link between Variant p.G602S and Type 2 Diabetes.	Florwick A	Frontiers in genetics	2017	PMID: 28663758
Reproducible Analysis of Post-Translational Modifications in Proteomes--Application to Human Mutations.	Holehouse AS	PloS one	2015	PMID: 26659599
Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations.	Scharner J	Human mutation	2011	PMID: 20848652
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LMNA	-	-	-	-

Text-mined citations for rs267607629 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_170707.4(LMNA):c.618C>G (p.Phe206Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267607629 ...