1-156115268-A-G

Variant names:

• chr1-156115268-A-G
• rs397517901
• NM_170707.4:c.350A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

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: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (1 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:22
• Conservation: PhyloP100: 5.13

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]

ACMG classification

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
LMNA	NM_170707.4	c.350A>G	p.Lys117Arg	missense_variant	Exon 1 of 12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.350A>G	p.Lys117Arg	missense_variant	Exon 1 of 10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.350A>G	p.Lys117Arg	missense_variant	Exon 1 of 12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.350A>G	p.Lys117Arg	missense_variant	Exon 1 of 10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152222 Hom.: 0 Cov.: 32

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

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

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

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:1 Uncertain:22

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4

Feb 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 14, 2016

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

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

- -

Jul 24, 2024

Athena Diagnostics

Significance: Uncertain significance

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

- -

Cardiomyopathy Uncertain:2

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. -

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

- -

not specified Uncertain:2

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. -

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. -

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. -

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. -

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. -

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

Other links and lift over

dbSNP: rs397517901; hg19: chr1-156085059;