rs58672172

chr1-156136251-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_170707.4(LMNA):c.1195C>T(p.Arg399Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,611,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R399H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6 O:1
• Conservation: PhyloP100: 0.179

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156136252-G-A is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, LMNA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMNA	NM_170707.4	c.1195C>T	p.Arg399Cys	missense_variant	7/12	ENST00000368300.9
LMNA	NM_005572.4	c.1195C>T	p.Arg399Cys	missense_variant	7/10	ENST00000677389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMNA	ENST00000368300.9	c.1195C>T	p.Arg399Cys	missense_variant	7/12	1	NM_170707.4	P1
LMNA	ENST00000677389.1	c.1195C>T	p.Arg399Cys	missense_variant	7/10		NM_005572.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248876 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134688

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459646 Hom.: 0 Cov.: 34 AF XY: 0.00000826 AC XY: 6 AN XY: 726180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74376

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary dilated cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This missense variant replaces arginine with cysteine at codon 399 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant does not change nuclear morphology or lamin A localization (PMID: 20160190). Another study has shown that this variant causes a moderate defect in the lamin A assembly, weakens the interaction between lamin A and NUP155, a key component of nuclear pore complexes, and reduces cardiac sodium channel density (PMID: 30488537). However, clinical relevance of these observations is not known. This variant has been reported in an individual affected with an early-onset dilated cardiomyopathy and in his unaffected mother (PMID: 30012837). This proband carried a pathogenic truncation variant in the TTN gene, which was inherited from his affected father. This variant has also been reported in an individual affected with familial partial lipodystrophy (PMID: 17250669) and in an individual affected with atrial fibrillation (PMID: 30488537). This variant has been identified in 3/248876 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. -
Uncertain significance, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

not provided Uncertain:1 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27841971, 28663758, 18585512, 20160190, 17250669, 30012837, 30488537) -

Charcot-Marie-Tooth disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Familial partial lipodystrophy, Dunnigan type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 15, 2023

This missense variant replaces arginine with cysteine at codon 399 of the lamin A/C proteins. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that this variant does not change nuclear morphology or lamin A localization (PMID: 20160190). Another study has shown that this variant causes a moderate defect in lamin A assembly, weakening the interaction between lamin A and NUP155, a key component of nuclear pore complexes, and reducing cardiac sodium channel density (PMID: 30488537). However, clinical relevance of these observations is not known. This variant has been reported in an individual affected with early-onset dilated cardiomyopathy and in his unaffected mother (PMID: 30012837). This proband also carried a pathogenic truncation variant in the TTN gene, which was inherited from his affected father. This variant has also been reported in an individual affected with familial partial lipodystrophy (PMID: 17250669) and in an individual affected with atrial fibrillation (PMID: 30488537). This variant has been identified in 3/248876 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. -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 25, 2023

ClinVar contains an entry for this variant (Variation ID: 14519). 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. Experimental studies have shown that this missense change affects LMNA function (PMID: 30488537). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LMNA protein function. This missense change has been observed in individual(s) with lipodystrophy and dilated cardiomyopathy (PMID: 17250699, 20160190). This variant is present in population databases (rs58672172, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 399 of the LMNA protein (p.Arg399Cys). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2021

The p.R399C variant (also known as c.1195C>T), located in coding exon 7 of the LMNA gene, results from a C to T substitution at nucleotide position 1195. The arginine at codon 399 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was originally reported in a patient with familial partial lipodystrophy (Lanktree M et al. Clin Genet. 2007;71(2):183-6). The p.R399C variant was also detected in a proband with severe dilated cardiomyopathy but not in his affected father; however, after subsequent analysis, a TTN A-band truncation was also reported in the proband and the affected father (Parks SB et al. Am Heart J. 2008;156(1):161-9; Cowan J et al. Circ Cardiovasc Genet. 2010;3(1):6-14; Cowan JR et al. Circ Genom Precis Med, 2018 07;11:e002038). In vitro studies using transiently expressed fusion constructs showed nuclear morphology and lamin A localization patterns of p.R399C were comparable with wild-type (Cowan et al 2010); additional functional studies suggested some interference with protein interactions involving NUP155; however, clinical impact was not determined (Han M et al. Hum. Mutat., 2019 03;40:310-325). Another alteration at the same codon, p.R399H (c.1196G>A), was reported in a patient with metabolic laminopathy (Decaudain A et al. J Clin Endocrinol Metab. 2007;92(12):4835-44). This amino acid position is not well conserved in all available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
CardioboostCm	Benign	0.0022
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.11
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.099
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.031	T
MutationAssessor	Benign	0.90	L;.;L;L;L;.;.;.;.
MutationTaster	Benign	0.76	A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.060	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.089	T;T;T;T;T;D;T;T;D
Sift4G	Benign	0.084	T;T;T;T;T;T;T;T;T
Polyphen		0.97	D;.;D;D;.;.;D;.;.
Vest4		0.54
MutPred		0.86		Loss of MoRF binding (P = 0.0323);Loss of MoRF binding (P = 0.0323);Loss of MoRF binding (P = 0.0323);Loss of MoRF binding (P = 0.0323);Loss of MoRF binding (P = 0.0323);.;.;.;.;
MVP		0.98
MPC		0.49
ClinPred		0.21	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.12
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs58672172; hg19: chr1-156106042;