NM_170707.4(LMNA):c.1129C>T (p.Arg377Cys) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Nov 21, 2023
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:: RCV000223811.15

Allele description [Variation Report for NM_170707.4(LMNA):c.1129C>T (p.Arg377Cys)]

NM_170707.4(LMNA):c.1129C>T (p.Arg377Cys)

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.1129C>T (p.Arg377Cys)

HGVS:

NC_000001.11:g.156136093C>T
NG_008692.2:g.58521C>T
NM_001257374.3:c.793C>T
NM_001282624.2:c.886C>T
NM_001282625.2:c.1129C>T
NM_001282626.2:c.1129C>T
NM_005572.4:c.1129C>T
NM_170707.4:c.1129C>TMANE SELECT
NM_170708.4:c.1129C>T
NP_001244303.1:p.Arg265Cys
NP_001269553.1:p.Arg296Cys
NP_001269554.1:p.Arg377Cys
NP_001269555.1:p.Arg377Cys
NP_005563.1:p.Arg377Cys
NP_005563.1:p.Arg377Cys
NP_733821.1:p.Arg377Cys
NP_733822.1:p.Arg377Cys
LRG_254t1:c.1129C>T
LRG_254t2:c.1129C>T
LRG_254:g.58521C>T
LRG_254p1:p.Arg377Cys
NC_000001.10:g.156105884C>T
NM_005572.3:c.1129C>T
NM_170707.2:c.1129C>T
NM_170707.3:c.1129C>T
c.1129C>T
p.(Arg377Cys)

Protein change:

R265C

Links:

dbSNP: rs397517889

NCBI 1000 Genomes Browser:

rs397517889

Molecular consequence:

NM_001257374.3:c.793C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282624.2:c.886C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282625.2:c.1129C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282626.2:c.1129C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_005572.4:c.1129C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170707.4:c.1129C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_170708.4:c.1129C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000280179	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Likely pathogenic (Mar 18, 2015)	germline	clinical testing
SCV000292600	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 21, 2023)	germline	clinical testing	Citation Link,
SCV000704169	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Dec 16, 2016)	germline	clinical testing	Citation Link,
SCV002022699	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 16, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005198675	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 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	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	5	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280179.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	not provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. LMNA p.Arg377Cys Given the case data and lack of presence in general population databases (reviewed below) we consider this variant as likely disease causing. The variant has been seen in at least five unrelated cases with cardiomyopathy or laminopathy in the literature. There is segregation data on family members in the reported cases. Astejada M. et al., 2008 reported c.1129 C>T in one Japanese individual with muscular dystrophy with nuclear envelopathy. No specific details were provided. Komaki H et al., 2011 reported R377C in one female who died at 7 yo from heart failure. She had an unsteady gate and a CK of 1000 at biopsy. Cardiac involvement included DCM diagnosed at 7 yo with an EF of 32%. She had joint contractures of her ankles and no respiratory dysfunction. Sylvius et al., 2011 reported c.1129C>T in two unrelated individuals. One was diagnosed at 42 yo after having difficulty climbing stairs. (S)he had pelvic and muscle weakness, axial muscle wasting, no contractures cardiomyopathy with CD and ICD and was last examined at age 56. The other patient was diagnosed at age 40 after having difficulty climbing stairs. (S)he also had pelvic muscle weakness with cardiac conduction defects and arrhythmia and their last reported evaluation before publication was at age 67. Van Rijsingen et al., 2013 reported this variant in one individual with this variant in their large cohort of LMNA mutation carriers but no individual data was provided. Similar changes at the same amino acid are summarized below: Charniot et al., 2003 reported a family harboring the R377H variant. 12 family members are positive for the R377H variant in lamin A. Of those, 11/12 have a DCM phenotype. The one unaffected individual is the youngest of the mutation positive family members at 21 yo. 4/10 evaluated mutation positive family members have a muscular phenotype, and 1/10 additional family members has a borderline study at age 33 yo. All of the individuals in their 30s and 40s had a reduced ejection fraction (<55%), while those in their 20s had ejection fractions in the 60s. Complete left bundle branch block was found in 5/8 evaluated individuals 4/8 also had some level of AV block (including two individuals who had both LBBB and AVB. 9/12 individuals had some level of AF and 4 had episodes of VT. Every mutation positive family member over the age of 21 had some form of conduction system disease. Muchir et al., 2000 reported a carribean family with the R377H variant. Eight individuals were evaluated. This family reported musculoskeletal, cardiomyopathy and AV conduction system defects. In silico analysis with PolyPhen-2 predicts the variant to be damaging. The argenine at codon is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon 377 and nearby codons. In total the variant has not been seen in individuals from publicly available population datasets. There is no variation at codon 377 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on Caucasian and African American individuals (as of October 29, 2014).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		5	not provided	not provided	not provided

From GeneDx, SCV000292600.11

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect via disruption of normal protein folding leading to LMNA aggregation (PMID: 34862408); This variant is associated with the following publications: (PMID: 15678000, 21840938, 20474083, 18035086, 10814726, 12920062, 16407522, 19124654, 18646565, 20576434, 24503780, 23183350, 26060040, 27532257, 23062543, 27506821, 12032588, 16386954, 21483645, 31410651, 31296281, 31447099, 30078822, 34930020, 35387801, 37652022, 34363016, 36548481, 35239206, 21632249, 10939567, 34862408)

#	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), SCV000704169.2

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

From Revvity Omics, Revvity, SCV002022699.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005198675.1

#	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: Sep 29, 2024

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