NM_170707.4(LMNA):c.1146C>T (p.Gly382=) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Jul 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000057239.27

Allele description [Variation Report for NM_170707.4(LMNA):c.1146C>T (p.Gly382=)]

NM_170707.4(LMNA):c.1146C>T (p.Gly382=)

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.1146C>T (p.Gly382=)

Other names:

p.G382G:GGC>GGT

HGVS:

NC_000001.11:g.156136110C>T
NG_008692.2:g.58538C>T
NM_001257374.3:c.810C>T
NM_001282624.2:c.903C>T
NM_001282625.2:c.1146C>T
NM_001282626.2:c.1146C>T
NM_005572.4:c.1146C>T
NM_170707.4:c.1146C>TMANE SELECT
NM_170708.4:c.1146C>T
NP_001244303.1:p.Gly270=
NP_001269553.1:p.Gly301=
NP_001269554.1:p.Gly382=
NP_001269555.1:p.Gly382=
NP_005563.1:p.Gly382=
NP_733821.1:p.Gly382=
NP_733822.1:p.Gly382=
LRG_254t2:c.1146C>T
LRG_254:g.58538C>T
NC_000001.10:g.156105901C>T
NM_170707.2:c.1146C>T
NM_170707.3:c.1146C>T
c.1146C>T

Links:

dbSNP: rs57508089

NCBI 1000 Genomes Browser:

rs57508089

Molecular consequence:

NM_001257374.3:c.810C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001282624.2:c.903C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001282625.2:c.1146C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001282626.2:c.1146C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_005572.4:c.1146C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_170707.4:c.1146C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_170708.4:c.1146C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000088352	Epithelial Biology; Institute of Medical Biology, Singapore	no classification provided	not provided	not provided	not provided
SCV000234694	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 1, 2024)	germline	clinical testing	Citation Link,
SCV000704410	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Jan 3, 2017)	germline	clinical testing	Citation Link,
SCV001926369	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV001954120	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV002503039	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 2, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17377071, 24915601, 25741868
SCV003916512	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Jul 1, 2024)	germline	clinical testing	Citation Link,
SCV005198676	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 24, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	9	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	3	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Phenotypic clustering of lamin A/C mutations in neuromuscular patients.

Benedetti S, Menditto I, Degano M, Rodolico C, Merlini L, D'Amico A, Palmucci L, Berardinelli A, Pegoraro E, Trevisan CP, Morandi L, Moroni I, Galluzzi G, Bertini E, Toscano A, Olivè M, Bonne G, Mari F, Caldara R, Fazio R, Mammì I, Carrera P, et al.

Neurology. 2007 Sep 18;69(12):1285-92. Epub 2007 Mar 21.

PubMed [citation]

PMID:: 17377071

Evaluation of damaging effects of splicing mutations: validation of an in vitro method for diagnostic laboratories.

Di Resta C, Manzoni M, Berisso MZ, Siciliano G, Benedetti S, Ferrari M.

Clin Chim Acta. 2014 Sep 25;436:276-82. doi: 10.1016/j.cca.2014.05.026. Epub 2014 Jun 7.

PubMed [citation]

PMID:: 24915601

See all PubMed Citations (3)

Details of each submission

From Epithelial Biology; Institute of Medical Biology, Singapore, SCV000088352.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	not provided	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not provided	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000234694.15

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Observed in association with limb-girdle muscular dystrophy, arrhythmia, and dilated cardiomyopathy (DCM) in individuals referred for genetic testing at GeneDx and in the published literature (PMID: 24503780, 17377071); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes splice predictors and evolutionary conservation, predict the creation of a strong cryptic splice donor site upstream of the natural donor site in intron 6; Published mRNA functional studies demonstrated creation of a cryptic splice donor site in the 3' end of exon 6, resulting in a deletion of the last 13 nucleotides of exon 6 and a premature stop codon 93 amino acids downstream (PMID: 17377071); This variant is associated with the following publications: (PMID: 27506821, 24915601, 28679633, 28798025, 29582363, 31447099, Ferradini2021[publication], 24503780, 17377071)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000704410.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		3	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001926369.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001954120.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002503039.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV003916512.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	not provided	clinical testing	not provided

Description

LMNA: PVS1:Strong, PM2, PS4:Moderate, PS3:Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		8	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198676.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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