1-156115268-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_170707.4(LMNA):​c.350A>G​(p.Lys117Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000038 in 1,605,706 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K117T) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 32)
Exomes š‘“: 0.000038 ( 1 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

1
9
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:22

Conservation

PhyloP100: 5.13
Variant links:
Genes affected
LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_170707.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the LMNA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 178 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 2.3673 (below the threshold of 3.09). Trascript score misZ: 3.0905 (above the threshold of 3.09). GenCC associations: The gene is linked to familial partial lipodystrophy, Dunnigan type, autosomal recessive Emery-Dreifuss muscular dystrophy, LMNA-related cardiocutaneous progeria syndrome, atrioventricular block, dilated cardiomyopathy 1A, Emery-Dreifuss muscular dystrophy 2, autosomal dominant, atypical Werner syndrome, restrictive dermopathy 1, autosomal semi-dominant severe lipodystrophic laminopathy, Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B1, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, mandibuloacral dysplasia with type A lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, heart-hand syndrome, Slovenian type, congenital muscular dystrophy due to LMNA mutation, lethal restrictive dermopathy, Hutchinson-Gilford progeria syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.37211412).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LMNANM_170707.4 linkc.350A>G p.Lys117Arg missense_variant Exon 1 of 12 ENST00000368300.9 NP_733821.1 P02545-1A0A384MQX1
LMNANM_005572.4 linkc.350A>G p.Lys117Arg missense_variant Exon 1 of 10 ENST00000677389.1 NP_005563.1 P02545-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LMNAENST00000368300.9 linkc.350A>G p.Lys117Arg missense_variant Exon 1 of 12 1 NM_170707.4 ENSP00000357283.4 P02545-1
LMNAENST00000677389.1 linkc.350A>G p.Lys117Arg missense_variant Exon 1 of 10 NM_005572.4 ENSP00000503633.1 P02545-2

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152222
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000560
AC:
13
AN:
232112
Hom.:
0
AF XY:
0.0000863
AC XY:
11
AN XY:
127434
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000592
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000200
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000379
Gnomad OTH exome
AF:
0.000172
GnomAD4 exome
AF:
0.0000378
AC:
55
AN:
1453484
Hom.:
1
Cov.:
31
AF XY:
0.0000581
AC XY:
42
AN XY:
723100
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000676
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000408
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000135
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152222
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000477
Hom.:
0
Bravo
AF:
0.0000604
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000496
AC:
6

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:22
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:4
Sep 14, 2016
Eurofins Ntd Llc (ga)
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 08, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2019
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 24, 2024
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 06, 2023
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiomyopathy Uncertain:2
Aug 25, 2020
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 10, 2025
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces lysine with arginine at codon 117 of the lamin A/C proteins. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 26752647, 2753225, 34935411, 37652022). Additionally, this variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 38757491) and in several individuals who had been investigated by a cardiologist and/or affected with possible cardiac events (PMID: 23183350). This variant has been identified in 16/263490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:2
Mar 15, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: LMNA c.350A>G (p.Lys117Arg) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-05 in 1605706 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in LMNA causing Cardiomyopathy (3.8e-05 vs 0.00025), allowing no conclusion about variant significance. c.350A>G has been reported in the literature in individuals affected with Cardiomyopathy (examples: Fontana_2013, Rijsingen_2013, Bayram_2016, Walsh_2017, Khan_2022, and McGurk_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. At-least one publication has reported experimental evidence that this variant does not increase aggregation compared to WT protein in HEK 293 cells or C2C12 myoblasts (Anderson_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34862408, 26752647, 23328570, 34935411, 37652022, 23183350, 27532257). ClinVar contains an entry for this variant (Variation ID: 48063). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jun 28, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Lys117Arg variant in LMNA has been previously reported in 2 individuals with DCM (one of whom carried an additional pathogenic variant in LMNA), 1 individual with LVNC, 1 individual with DCM and LVNC, and in 2 individuals with unspecified cardiomyopathy and was found to segregate with disease in 2 affected family members with LVNC from 1 family (Botto 2011, Rijsingen 2013, Fontana 2013, LMM data). This variant was also identified in the homozygous state in 1 individual with DCM and arthrogryposis (Bayram 2016). It has been identified in 0.02% (6/29936) of South Asian chromosomes by gnomAD (http://gnomAD.broadinstitute.org/). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Lys117Arg variant is uncertain. ACMG/AMP Criteria Applied: None. -

Emery-Dreifuss muscular dystrophy 2, autosomal dominant Uncertain:2
-
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Aug 24, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1857829:Heart-hand syndrome, Slovenian type Uncertain:1
Nov 12, 2021
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

- -

Charcot-Marie-Tooth disease type 2B1 Uncertain:1
Aug 24, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Congenital muscular dystrophy due to LMNA mutation Uncertain:1
Aug 24, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dilated cardiomyopathy 1A Uncertain:1
Aug 24, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hypertrophic cardiomyopathy Uncertain:1
Mar 17, 2017
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: research

The LMNA Lys117Arg variant has been previously reported in multiple probands with various conditions. Botto et al., report this variant in 1 LVNC proband and their 2 daughters with mild LVNC (2011). It has also been reported in 2 DCM probands (Fontana M, et al., 2013; Pugh TJ, et al., 2014) it is important to note that one of the DCM probands also carried another pathogenic LMNA variant (Pugh TJ, et al., 2014). A patient with arthrogryposis features; contractures of hands and feet, myopathy, hypotonia, and dilated cardiomyopathy, was found to be harbouring both LMNA Lys117Arg and RIPK4 Val561Met in the homozygous form (Bayram Y, et al., 2016). The variant has also been reported in 2 Brugada syndrome patients (Pietrelli A, 2013) and in a Hispanic child with LVNC/DCM (LMM, ClinVar SCV000065039.4). Finally, we identified this variant in a male of Lebanese ethnicity with severe hypertrophic cardiomyopathy. The variant is present in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at an allele frequency >0.00006 which is higher then expected for an inherited heart condition. Predictions from in silico tools are conflicting (SIFT "Tolerated"; PolyPhen-2 "Benign; MutationTaster "Disease causing"). In summary, based on the lack of evidence to associate a LMNA variant as a causative gene in HCM and the elevated allele frequency, we classify LMNA Lys117Arg as a variant of 'uncertain signifigance'. -

Mandibuloacral dysplasia with type A lipodystrophy Uncertain:1
Aug 24, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Charcot-Marie-Tooth disease type 2 Uncertain:1
Jan 17, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 117 of the LMNA protein (p.Lys117Arg). This variant is present in population databases (rs397517901, gnomAD 0.02%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 2338570, 23183350, 26752647, 27532257, 34935411, 37652022). ClinVar contains an entry for this variant (Variation ID: 48063). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect LMNA function (PMID: 34862408). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Lethal tight skin contracture syndrome Uncertain:1
Aug 24, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules Uncertain:1
Aug 24, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Primary dilated cardiomyopathy Uncertain:1
Jun 11, 2024
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces lysine with arginine at codon 117 of the lamin A/C proteins. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with dilated cardiomyopathy (PMID: 26752647, 2753225, 34935411). Additionally, this variant has been reported in three individuals who had been investigated by a cardiologist and/or affected with possible cardiac events (PMID: 23183350). This variant has been identified in 16/263490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Familial partial lipodystrophy, Dunnigan type Uncertain:1
Dec 04, 2023
Clinical Genomics Laboratory, Washington University in St. Louis
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

An LMNA c.350A>G (p.Lys117Arg) variant was identified. This variant has been published in the literature in relation to cardiac disease and arthrogryposis, but to our knowledge, has not been reported in association with diabetes. This variant has been reported in the ClinVar database as a variant of uncertain significance by numerous submitters. It is observed on 61/1,605,706 alleles in the general population (gnomAD v.4.0.0). including one homozygote. Computational predictors are uncertain as to the impact of this variant on LMNA function. Due to conflicting information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

Cardiovascular phenotype Uncertain:1
Dec 18, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.K117R variant (also known as c.350A>G), located in coding exon 1 of the LMNA gene, results from an A to G substitution at nucleotide position 350. The lysine at codon 117 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in several dilated cardiomyopathy (DCM) and LMNA-related cardiomyopathy cohorts; however, clinical details were limited (Fontana M et al. JACC Cardiovasc Imaging. 2013;6:124-6; Pugh TJ et al. Genet. Med. 2014;16:601-8; Walsh R et al. Genet. Med. 2017;19:192-203; Peretto G et al. Ann Intern Med, 2019 10;171:458-463; Khan RS et al. J Am Heart Assoc. 2022 Jan;11(1):e022854). This variant was also detected in the homozygous state in an individual with arthrogryposis and DCM; however, the individual was homozygous for a missense variant in the RIPK4 gene (p.V561M) as well (Bayram Y et al. J. Clin. Invest. 2016;126:762-78). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
CardioboostCm
Uncertain
0.14
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
29
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.56
.;.;.;D;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.032
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.89
D;D;D;D;D
M_CAP
Uncertain
0.089
D
MetaRNN
Benign
0.37
T;T;T;T;T
MetaSVM
Benign
-0.70
T
MutationAssessor
Benign
1.1
L;.;L;L;L
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-0.20
N;N;N;N;N
REVEL
Uncertain
0.45
Sift
Benign
0.65
T;T;T;T;T
Sift4G
Benign
0.70
T;T;T;T;T
Polyphen
0.019
B;.;B;B;.
Vest4
0.70
MutPred
0.47
Loss of ubiquitination at K117 (P = 0.0309);Loss of ubiquitination at K117 (P = 0.0309);Loss of ubiquitination at K117 (P = 0.0309);Loss of ubiquitination at K117 (P = 0.0309);Loss of ubiquitination at K117 (P = 0.0309);
MVP
0.99
MPC
0.80
ClinPred
0.25
T
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.35
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397517901; hg19: chr1-156085059; API