NM_170707.3(LMNA):c.949G>A (p.Glu317Lys) AND Primary dilated cardiomyopathy

Clinical significance:Likely pathogenic (Last evaluated: Apr 10, 2014)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000041379.2

Allele description [Variation Report for NM_170707.3(LMNA):c.949G>A (p.Glu317Lys)]

NM_170707.3(LMNA):c.949G>A (p.Glu317Lys)

Gene:
LMNA:lamin A/C [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q22
Genomic location:
Preferred name:
NM_170707.3(LMNA):c.949G>A (p.Glu317Lys)
HGVS:
  • NC_000001.11:g.156135913G>A
  • NG_008692.2:g.58341G>A
  • NM_005572.3:c.949G>A
  • NM_170707.3:c.949G>A
  • NM_170708.3:c.949G>A
  • NP_005563.1:p.Glu317Lys
  • NP_733821.1:p.Glu317Lys
  • NP_733822.1:p.Glu317Lys
  • LRG_254t1:c.949G>A
  • LRG_254:g.58341G>A
  • LRG_254p1:p.Glu317Lys
  • LRG_254p2:p.Glu317Lys
  • LRG_254p3:p.Glu317Lys
  • NC_000001.10:g.156105704G>A
  • NM_170707.2:c.949G>A
  • P02545:p.Glu317Lys
  • c.949G>A
Protein change:
E317K
Links:
UniProtKB: P02545#VAR_039775; dbSNP: 56816490
NCBI 1000 Genomes Browser:
rs56816490
Molecular consequence:
  • NM_170707.3:c.949G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
4

Condition(s)

Name:
Primary dilated cardiomyopathy (DCM)
Synonyms:
Congestive cardiomyopathy
Identifiers:
EFO: EFO_0000407; MedGen: C0007193; Human Phenotype Ontology: HP:0001644

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000065072Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely pathogenic
(Apr 10, 2014)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided94not providednot providednot providedclinical testing

Citations

PubMed

Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease.

Arbustini E, Pilotto A, Repetto A, Grasso M, Negri A, Diegoli M, Campana C, Scelsi L, Baldini E, Gavazzi A, Tavazzi L.

J Am Coll Cardiol. 2002 Mar 20;39(6):981-90.

PubMed [citation]
PMID:
11897440

Long-term outcome and risk stratification in dilated cardiolaminopathies.

Pasotti M, Klersy C, Pilotto A, Marziliano N, Rapezzi C, Serio A, Mannarino S, Gambarin F, Favalli V, Grasso M, Agozzino M, Campana C, Gavazzi A, Febo O, Marini M, Landolina M, Mortara A, Piccolo G, Viganò M, Tavazzi L, Arbustini E.

J Am Coll Cardiol. 2008 Oct 7;52(15):1250-60. doi: 10.1016/j.jacc.2008.06.044.

PubMed [citation]
PMID:
18926329
See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine, SCV000065072.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided9not providednot providedclinical testing PubMed (4)

Description

The Glu317Lys variant in LMNA has been reported in at least 2 individuals with DCM and atrioventricular block and in 1 individual with DCM, and segregated with disease in at least 1 affected relative (Arbustini 2002, Pasotti 2008, Millat 2009 – please note, there is likely overlap between the individuals reported by these studies). In addition, this variant has been identified by our laboratory in 3 families with DCM and arrhythmia, segregating with disease in one affected relative, and in 1 individual with AV block and a family history of SCD. Data from large population studies is insufficient to assess the frequency of this variant. Computational prediction tools and conservation analysis suggest that the Glu317Lys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Variants in LMNA are prevalent in individuals with DCM and conduction system disease/arrhythmia and the presence of conduction system disease in all but 1 family with this variant increases the likelihood that it is pathogenic. In summary, the Glu317Lys variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided9not provided4not provided

Last Updated: Apr 9, 2018