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NM_170707.4(LMNA):c.872A>T (p.Glu291Val) AND Dilated cardiomyopathy 1A

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Apr 20, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003228574.1

Allele description [Variation Report for NM_170707.4(LMNA):c.872A>T (p.Glu291Val)]

NM_170707.4(LMNA):c.872A>T (p.Glu291Val)

Gene:
LMNA:lamin A/C [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q22
Genomic location:
Preferred name:
NM_170707.4(LMNA):c.872A>T (p.Glu291Val)
HGVS:
  • NC_000001.11:g.156135248A>T
  • NG_008692.2:g.57676A>T
  • NM_001257374.3:c.536A>T
  • NM_001282624.2:c.629A>T
  • NM_001282625.2:c.872A>T
  • NM_001282626.2:c.872A>T
  • NM_001406983.1:c.872A>T
  • NM_001406984.1:c.872A>T
  • NM_001406985.1:c.872A>T
  • NM_001406986.1:c.629A>T
  • NM_001406987.1:c.629A>T
  • NM_001406988.1:c.575A>T
  • NM_001406989.1:c.536A>T
  • NM_001406990.1:c.314A>T
  • NM_001406991.1:c.872A>T
  • NM_001406992.1:c.872A>T
  • NM_001406993.1:c.314A>T
  • NM_001406994.1:c.208A>T
  • NM_001406995.1:c.314A>T
  • NM_001406996.1:c.314A>T
  • NM_001406997.1:c.314A>T
  • NM_001406998.1:c.536A>T
  • NM_001406999.1:c.208A>T
  • NM_001407000.1:c.208A>T
  • NM_001407001.1:c.208A>T
  • NM_001407002.1:c.314A>T
  • NM_001407003.1:c.314A>T
  • NM_005572.4:c.872A>T
  • NM_170707.4:c.872A>TMANE SELECT
  • NM_170708.4:c.872A>T
  • NP_001244303.1:p.Glu179Val
  • NP_001269553.1:p.Glu210Val
  • NP_001269554.1:p.Glu291Val
  • NP_001269555.1:p.Glu291Val
  • NP_001393912.1:p.Glu291Val
  • NP_001393913.1:p.Glu291Val
  • NP_001393914.1:p.Glu291Val
  • NP_001393915.1:p.Glu210Val
  • NP_001393916.1:p.Glu210Val
  • NP_001393917.1:p.Glu192Val
  • NP_001393918.1:p.Glu179Val
  • NP_001393919.1:p.Glu105Val
  • NP_001393920.1:p.Glu291Val
  • NP_001393921.1:p.Glu291Val
  • NP_001393922.1:p.Glu105Val
  • NP_001393923.1:p.Ser70Cys
  • NP_001393924.1:p.Glu105Val
  • NP_001393925.1:p.Glu105Val
  • NP_001393926.1:p.Glu105Val
  • NP_001393927.1:p.Glu179Val
  • NP_001393928.1:p.Ser70Cys
  • NP_001393929.1:p.Ser70Cys
  • NP_001393930.1:p.Ser70Cys
  • NP_001393931.1:p.Glu105Val
  • NP_001393932.1:p.Glu105Val
  • NP_005563.1:p.Glu291Val
  • NP_005563.1:p.Glu291Val
  • NP_733821.1:p.Glu291Val
  • NP_733821.1:p.Glu291Val
  • NP_733822.1:p.Glu291Val
  • NP_733822.1:p.Glu291Val
  • LRG_254t1:c.872A>T
  • LRG_254t2:c.872A>T
  • LRG_254t3:c.872A>T
  • LRG_254:g.57676A>T
  • LRG_254p1:p.Glu291Val
  • LRG_254p2:p.Glu291Val
  • LRG_254p3:p.Glu291Val
  • NC_000001.10:g.156105039A>T
  • NM_005572.3:c.872A>T
  • NM_170707.2:c.872A>T
  • NM_170708.2:c.872A>T
  • NR_047544.1:n.1513A>T
  • NR_047545.1:n.760A>T
Protein change:
E105V
Molecular consequence:
  • NM_001257374.3:c.536A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282624.2:c.629A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282625.2:c.872A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001282626.2:c.872A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406983.1:c.872A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406984.1:c.872A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406985.1:c.872A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406986.1:c.629A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406987.1:c.629A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406988.1:c.575A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406989.1:c.536A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406990.1:c.314A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406991.1:c.872A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406992.1:c.872A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406993.1:c.314A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406994.1:c.208A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406995.1:c.314A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406996.1:c.314A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406997.1:c.314A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406998.1:c.536A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001406999.1:c.208A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407000.1:c.208A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407001.1:c.208A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407002.1:c.314A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001407003.1:c.314A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005572.4:c.872A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170707.4:c.872A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_170708.4:c.872A>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Dilated cardiomyopathy 1A (CMD1A)
Synonyms:
CARDIOMYOPATHY, CONGESTIVE; CARDIOMYOPATHY, DILATED, WITH CONDUCTION DEFECT 1; Idiopathic dilated cardiomyopathy; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007269; MedGen: C1449563; Orphanet: 300751; OMIM: 115200

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003925109New York Genome Center
criteria provided, single submitter

(NYGC Assertion Criteria 2020)		Likely pathogenic
(Apr 20, 2022) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedclinical testing

Details of each submission

From New York Genome Center, SCV003925109.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.872A>T (p.Glu291Val) variant identified in the LMNA gene substitutes a well conserved Glutamic Acid for Valine at amino acid291/665 (exon 5/12). This variant is absent from population databases (gnomADv3.1.2, BRAVO-TOPMed Freeze 8, All of Us) suggesting it is not a common benign variant in the populations represented in those databases. In silico algorithms predict this variant to be Pathogenic (REVEL; score:0.9509). While the p.Glu291Val variant identified here is absent from ClinVar, a different variant at the same amino acid position, p.Glu291Lys has been reported as Pathogenic in ClinVar(VarID:200942), and reported in multiple individuals in the literature with arrhythmias, dilated cardiomyopathy, and conduction disease or heart block [PMID:25498755, 32413188]. The p.Glu291Val variant has not been previously reported in the literature in affected individuals. The p.Glu291 residue is within the Coil 2 region of the Rod domain of LMNA (UniProtKB:P02545), and other missense variants in this region have been reported in individuals with LMNA-associated cardiac phenotypes [PMID:32413188, 30402260]. Given its absence in population databases, in silico algorithms strongly predict a damaging effect to the protein, and the presence of different pathogenic missense change at the same amino acid (p.Glu291Lys), the c.872A>T (p.Glu291Val) variant identified in the LMNA gene is reported as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

Last Updated: May 27, 2023