VCV002883981.1 - ClinVar

NM_170707.4(LMNA):c.460G>A (p.Glu154Lys)

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.

(1)

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.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_170707.4(LMNA):c.460G>A (p.Glu154Lys)

Variation ID: 2883981 Accession: VCV002883981.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 156130720 (GRCh38) [ NCBI UCSC ] 1: 156100511 (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 20, 2024	Feb 20, 2024	Oct 24, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_170707.4:c.460G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_733821.1:p.Glu154Lys	missense
NM_005572.4:c.460G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005563.1:p.Glu154Lys	missense
NM_001257374.3:c.124G>A	NP_001244303.1:p.Glu42Lys	missense
NM_001282624.2:c.217G>A	NP_001269553.1:p.Glu73Lys	missense
NM_001282625.2:c.460G>A	NP_001269554.1:p.Glu154Lys	missense
NM_001282626.2:c.460G>A	NP_001269555.1:p.Glu154Lys	missense
NM_001406983.1:c.460G>A	NP_001393912.1:p.Glu154Lys	missense
NM_001406984.1:c.460G>A	NP_001393913.1:p.Glu154Lys	missense
NM_001406985.1:c.460G>A	NP_001393914.1:p.Glu154Lys	missense
NM_001406986.1:c.217G>A	NP_001393915.1:p.Glu73Lys	missense
NM_001406987.1:c.217G>A	NP_001393916.1:p.Glu73Lys	missense
NM_001406988.1:c.163G>A	NP_001393917.1:p.Glu55Lys	missense
NM_001406989.1:c.124G>A	NP_001393918.1:p.Glu42Lys	missense
NM_001406990.1:c.-45-3683G>A		intron variant
NM_001406991.1:c.460G>A	NP_001393920.1:p.Glu154Lys	missense
NM_001406992.1:c.460G>A	NP_001393921.1:p.Glu154Lys	missense
NM_001406993.1:c.-99G>A		5 prime UTR
NM_001406994.1:c.-205G>A		5 prime UTR
NM_001406995.1:c.-45-3683G>A		intron variant
NM_001406996.1:c.-99G>A		5 prime UTR
NM_001406997.1:c.-99G>A		5 prime UTR
NM_001406998.1:c.124G>A	NP_001393927.1:p.Glu42Lys	missense
NM_001406999.1:c.-205G>A		5 prime UTR
NM_001407000.1:c.-205G>A		5 prime UTR
NM_001407001.1:c.-151-3683G>A		intron variant
NM_001407002.1:c.-45-3683G>A		intron variant
NM_001407003.1:c.-99G>A		5 prime UTR
NM_170708.4:c.460G>A	NP_733822.1:p.Glu154Lys	missense
NR_047544.1:n.1101G>A
NR_047545.1:n.348G>A
NC_000001.11:g.156130720G>A
NC_000001.10:g.156100511G>A
NG_008692.2:g.53148G>A
NG_082201.1:g.919G>A
LRG_254:g.53148G>A
LRG_254t1:c.460G>A	LRG_254p1:p.Glu154Lys
LRG_254t2:c.460G>A	LRG_254p2:p.Glu154Lys
LRG_254t3:c.460G>A	LRG_254p3:p.Glu154Lys

... more HGVS ... less HGVS

Protein change

E154K, E42K, E55K, E73K

Other names

Canonical SPDI

NC_000001.11:156130719: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.

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

Links

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
LOC126805877	-	-	-	GRCh38	-	157

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.
Charcot-Marie-Tooth disease type 2	Uncertain significance (1)	criteria provided, single submitter	Oct 24, 2023	RCV003743411.2

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.
Uncertain significance (Oct 24, 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: SCV004509392.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 31303467 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 154 of the LMNA protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 154 of the LMNA protein (p.Glu154Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31303467). 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 with a positive predictive value of 95%. 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)

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 154 of the LMNA protein (p.Glu154Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31303467). 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 with a positive predictive value of 95%. 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.

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
Genetic variants identified by target next-generation sequencing in heart transplant patients with dilated cardiomyopathy.	Martins E	Revista portuguesa de cardiologia	2019	PMID: 31303467

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_170707.4(LMNA):c.460G>A (p.Glu154Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...