rs794728588

Positions:

• chr1-156115262-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The ENST00000368300.9(LMNA):​c.344A>T​(p.Glu115Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. E115K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LMNA ENST00000368300.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 5.10

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 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in ENST00000368300.9
• 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.
• PP5: Variant 1-156115262-A-T is Pathogenic according to our data. Variant chr1-156115262-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200932.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LMNA	NM_170707.4	c.344A>T	p.Glu115Val	missense_variant	1/12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.344A>T	p.Glu115Val	missense_variant	1/10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.344A>T	p.Glu115Val	missense_variant	1/12	1	NM_170707.4	ENSP00000357283	P1
LMNA	ENST00000677389.1	c.344A>T	p.Glu115Val	missense_variant	1/10		NM_005572.4	ENSP00000503633

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 11, 2013

p.Glu115Val (GAG>GTG): c.344 A>T in exon 1 of the LMNA gene (NM_170707.2). The Glu115Val variant in the LMNA gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu115Val results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a non-polar Valine at a position that is conserved across species. In silico analysis predicts Glu115Val is damaging to the protein structure/function. Mutations in nearby residues (Leu102Pro, Gly125Ala) have been reported in association with laminopathy, further supporting the functional importance of this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Glu115Val was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In summary, while Glu115Val is a good candidate for a disease-causing mutation, with the information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in DCM panel(s). -

Peripheral neuropathy;C0340427:Primary familial dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jun 03, 2019

- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Jan 26, 2013

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.Glu115Val Based on the data reviewed below we consider it a variant of uncertain significance. We did find one online listing of the variant (http://cardiogenetics.nl/MVD/variants.php?select_db=LMNA&action=view&view=0000151%2C0000383%2C0). Unfortunately no clinical information is provided either about the specific individual with that variant or the cohort studied. This is a non conservative amino acid change with a negatively charged Glutamic Acid replaced with a nonpolar, neutral Valine at a residue that is highly conserved across species (with the exception of elegans and drosophila). In silico analysis with PolyPhen-2 predicts the amino acid change to be possibly damaging. Mutation taster predicts it to be disease causing. Variants in nearby codons have been reported in association with laminoapthy (p.Leu102Pro, p.Arg110Ser, p.Glu111Lys, p.Lys117Arg, p.Gly125Ala) (Stenson P et al 2009, Dittmer et al 2011, http://www.umd.be/LMNA/). There also appears to be minimal variation in this region in the general population. The nearest missense variants in the NHLBI Exome Sequencing Project are at codons 147, 166, 175, and 189, which each only occurring in 1 out of ~6500 individuals (as of January 27th, 2013). In total, the variant has not been observed in ~6500 individuals from publicly available datasets roughly representing the general population. The variant is not listed in dbSNP or 1000 Genomes (as of January 27th, 2013). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of January 25th 2013). -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 02, 2022

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 200932). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 115 of the LMNA protein (p.Glu115Val). -

Dilated cardiomyopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 21, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a glutamic acid to a valine (exon 1). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0504 - Same amino acid change has been observed in mammals. (B) 0600 - Variant is located in an annotated domain or motif (Intermediate filament protein; NCBI). (N) 0708 - Comparable variants have conflicting previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a methionine has also been classified as a variant of uncertain significance (PMID: 29237675). (N) 0808 - Previous reports of pathogenicity are conflicting. The variant has been previously reported as both likely pathogenic and a variant of uncertain significance in ClinVar. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
CardioboostCm	Uncertain	0.14
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	.;.;.;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.58	D;D;D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.2	M;.;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		0.93	P;.;D;P;.
Vest4		0.35
MutPred		0.55		Loss of ubiquitination at K114 (P = 0.0247);Loss of ubiquitination at K114 (P = 0.0247);Loss of ubiquitination at K114 (P = 0.0247);Loss of ubiquitination at K114 (P = 0.0247);Loss of ubiquitination at K114 (P = 0.0247);
MVP		0.92
MPC		2.2
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.86
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs794728588; hg19: chr1-156085053;