rs121912493

Positions:

• chr1-156136374-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_170707.4(LMNA):​c.1318G>A​(p.Val440Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000168 in 1,611,684 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).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (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: 3.94

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]

LMNA (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_170707.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LMNA. . Gene score misZ 2.3673 (greater than the threshold 3.09). Trascript score misZ 3.0905 (greater than threshold 3.09). GenCC has associacion of gene with 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.1318G>A	p.Val440Met	missense_variant	7/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.1318G>A	p.Val440Met	missense_variant	7/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.1318G>A	p.Val440Met	missense_variant	7/12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.1318G>A	p.Val440Met	missense_variant	7/10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152214 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1459470 Hom.: 0 Cov.: 34 AF XY: 0.0000138 AC XY: 10 AN XY: 726022

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	- -

Mandibuloacral dysplasia with type A lipodystrophy, atypical Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2007

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 17, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMNA function (PMID: 17848409). 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) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function. ClinVar contains an entry for this variant (Variation ID: 14520). This missense change has been observed in individual(s) with autosomal recessive mandibuloacral dysplasia and/or the severe form of autosomal recessive familial partial lipodystrophy (FPLD) (PMID: 10999845, 17848409). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant dilated cardiomyopathy and/or autosomal dominant Hutchinson–Gilford progeria syndrome (PMID: 19875404, 25371241, 30871747); however, the role of the variant in this condition is currently unclear. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 440 of the LMNA protein (p.Val440Met). -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 27, 2020

Variant summary: LMNA c.1318G>A (p.Val440Met) results in a conservative amino acid change located in the Lamin tail domain (IPR001322) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248838 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1318G>A has been reported in the literature in individuals affected with Dilated Cardiomyopathy (e.g. Moller_2009, Sousa_2019, Martins_2019), but also unaffected family members (e.g. Moller_2009). The variant has also been reported in a compound heterozygous state with a pathogenic variant in an individual diagnosed with Mandibuloacral dysplasia type A (MADA), consistent with an autosomal recessive pattern of inhertiance for this disease (e.g. Lombardi_2007). Other reports in the literature include the variant in a compound heterozygous state with another pathogenic variant in LMNA in an individual with a severe form of Dunnigan-type partial lipodystrophy (FPLD, Hegele_2000), leading the authors to suggest that the variant may modify this phenotype, and in an individual with Hutchinson-Gilford Progeria Syndrome (HGPD, Zhang_2016). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Several publications report experimental evidence evaluating an impact on protein function, however, do not allow convincing conclusions about the variant effect (e.g. Nitta_2006, Lombardi_2007, Dittmer_2014). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as uncertain significance. Based on the evidence outlined above, until additional information becomes available, the variant was classified as uncertain significance. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jul 21, 2022

This missense variant replaces valine with methionine at codon 440 of the LMNA protein and is located in the lamin tail domain that is involved in binding to DNA and other proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that cells carrying this variant in the compound heterozygous state display altered nuclear morphology and heterochromatin organization (PMID: 17848409) and that this variant may affect interaction with other proteins (PMID: 24623722). However, the clinical relevance of these observations is not known. This variant has also been reported in heterozygosity in 2 individuals with dilated cardiomyopathy (PMID: 19875404, 30871747) and in an individual affected with Hutchinson-Gilford progeria syndrome (PMID: 25371241). This variant has been reported in compound heterozygosity in an individual affected with Dunnigan-type partial lipodystrophy (PMID: 10999845) and in an individual affected with mandibuloacral dysplasia type A-like phenotype (PMID: 17848409). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 20, 2024

This missense variant replaces valine with methionine at codon 440 of the LMNA protein and is located in the lamin tail domain that is involved in binding to DNA and other proteins. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. Functional studies have shown that cells carrying this variant in the compound heterozygous state display altered nuclear morphology and heterochromatin organization (PMID: 17848409) and that this variant may affect interaction with other proteins (PMID: 24623722). However, the clinical relevance of these observations is not known. This variant has also been reported in heterozygosity in two individuals with dilated cardiomyopathy (PMID: 19875404, 30871747), in an individual affected with hypertrophic cardiomyopathy (PMID: 38489124), and in an individual affected with Hutchinson-Gilford progeria syndrome (PMID: 25371241). This variant has been reported in compound heterozygosity in an individual affected with Dunnigan-type partial lipodystrophy (PMID: 10999845) and in an individual affected with mandibuloacral dysplasia type A-like phenotype (PMID: 17848409). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in autosomal dominant cardiomyopathy conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 17, 2023

The p.V440M variant (also known as c.1318G>A), located in coding exon 7 of the LMNA gene, results from a G to A substitution at nucleotide position 1318. The valine at codon 440 is replaced by methionine, an amino acid with highly similar properties. This variant has been detected in the compound heterozygous state (in trans) with the p.R482Q mutation in a proband with a severe form of familial partial lipodystrophy; however, the proband's mother who had only the p.V440M allele was reportedly unaffected (Hegele RA et al. J Clin Endocrinol Metab, 2000 Sep;85:3431-5). This variant was also seen in compound heterozygosity with the p.R527H mutation in an individual with an atypical mandibulosacral dysplasia type A-like presentation (Lombardi F et al. J Clin Endocrinol Metab, 2007 Nov;92:4467-71). This variant has also been detected in the heterozygous state in a proband with Hutchinson-Gilford progeria syndrome with scleroderma-like skin changes (Zhang S et al. J Eur Acad Dermatol Venereol, 2016 Mar;30:463-5), and in the heterozygous state in an individual with dilated cardiomyopathy; however, two relatives with this variant were unaffected (Møller DV et al. Eur J Heart Fail, 2009 Nov;11:1031-5). This variant was detected in an additional dilated cardiomyopathy case; however, additional LMNA variants were also detected (Martins E et al. Rev Port Cardiol, 2019 06;38:441-447). In in vitro studies, cell lines with both p.V440M and p.R527H displayed abnormal nuclear morphology; however, no significant anomalies were apparent in transfected cells with p.V440M alone (Lombardi F et al. J Clin Endocrinol Metab, 2007 Nov;92:4467-71). Another study indicated this variant may impact protein-protein interactions; however, relevance of this finding is unclear (Dittmer TA et al. Mol Biol Cell, 2014 May;25:1493-510). 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	Pathogenic	0.94
CardioboostCm	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;.;D;.;.;.;.;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;M;M;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.5	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;.;D;.;.
Vest4		0.76
MutPred		0.78		Gain of MoRF binding (P = 0.0889);Gain of MoRF binding (P = 0.0889);Gain of MoRF binding (P = 0.0889);Gain of MoRF binding (P = 0.0889);.;.;.;.;
MVP		0.94
MPC		1.1
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.75
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs121912493; hg19: chr1-156106165;