VCV001027845.4 - ClinVar

NM_170707.4(LMNA):c.133T>C (p.Tyr45His)

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.

(3)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_170707.4(LMNA):c.133T>C (p.Tyr45His)

Variation ID: 1027845 Accession: VCV001027845.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q22 1: 156115051 (GRCh38) [ NCBI UCSC ] 1: 156084842 (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	Mar 22, 2021	Feb 14, 2024	Jan 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_170707.4:c.133T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_733821.1:p.Tyr45His	missense
NM_005572.4:c.133T>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005563.1:p.Tyr45His	missense
NM_001282625.2:c.133T>C	NP_001269554.1:p.Tyr45His	missense
NM_001282626.2:c.133T>C	NP_001269555.1:p.Tyr45His	missense
NM_170708.4:c.133T>C	NP_733822.1:p.Tyr45His	missense
NC_000001.11:g.156115051T>C
NC_000001.10:g.156084842T>C
NG_008692.2:g.37479T>C
LRG_254:g.37479T>C

... more HGVS ... less HGVS

Protein change

Y45H

Other names

Canonical SPDI

NC_000001.11:156115050:T:C

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

dbSNP: rs1649714371 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.
Dilated cardiomyopathy 1A	Uncertain significance (1)	criteria provided, single submitter	Jan 17, 2020	RCV001328735.1
Congenital muscular dystrophy due to LMNA mutation	Uncertain significance (1)	criteria provided, single submitter	-	RCV001823197.3
Charcot-Marie-Tooth disease type 2	Likely pathogenic (1)	criteria provided, single submitter	Jan 3, 2024	RCV003581785.2

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 (Jan 17, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1A Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001519920.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital muscular dystrophy due to LMNA mutation Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002073345.1 First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022	Comment: The missense variant p.Y45H in LMNA (NM_170707.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The … (more) The missense variant p.Y45H in LMNA (NM_170707.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Y45H variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant was found in ClinVar with a classification of Uncertain Significance. The p.Y45H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The tyrosine residue at codon 45 of LMNA is conserved in all mammalian species. The nucleotide c.133 in LMNA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. (less) Clinical Features: Myopathy (present)
Likely pathogenic (Jan 03, 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: SCV004260828.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 10939567‚ 20848652‚ 23183350‚ 31434876 Comment: This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 45 of the LMNA protein (p.Tyr45His). … (more) This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 45 of the LMNA protein (p.Tyr45His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1027845). 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%. This variant disrupts the p.Tyr45 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10939567, 20848652, 23183350, 31434876; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)

Comment:

The missense variant p.Y45H in LMNA (NM_170707.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Y45H variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant was found in ClinVar with a classification of Uncertain Significance. The p.Y45H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The tyrosine residue at codon 45 of LMNA is conserved in all mammalian species. The nucleotide c.133 in LMNA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 45 of the LMNA protein (p.Tyr45His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 1027845). 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%. This variant disrupts the p.Tyr45 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10939567, 20848652, 23183350, 31434876; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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
Structural basis for lamin assembly at the molecular level.	Ahn J	Nature communications	2019	PMID: 31434876
Gender-specific differences in major cardiac events and mortality in lamin A/C mutation carriers.	van Rijsingen IA	European journal of heart failure	2013	PMID: 23183350
Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations.	Scharner J	Human mutation	2011	PMID: 20848652
Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene.	Bonne G	Annals of neurology	2000	PMID: 10939567

Text-mined citations for rs1649714371 ...

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.133T>C (p.Tyr45His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1649714371 ...