1-156115274-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate

The NM_170707.4(LMNA):​c.356G>T​(p.Arg119Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R119P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

LMNA
NM_170707.4 missense, splice_region

Scores

10
9
1
Splicing: ADA: 0.9999
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.89
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]

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ACMG classification

Classification made for transcript

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 0 benign, 16 uncertain in NM_170707.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-156115274-G-A is described in Lovd as [Likely_pathogenic].
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.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LMNANM_170707.4 linkc.356G>T p.Arg119Leu missense_variant, splice_region_variant Exon 1 of 12 ENST00000368300.9 NP_733821.1 P02545-1A0A384MQX1
LMNANM_005572.4 linkc.356G>T p.Arg119Leu missense_variant, splice_region_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.356G>T p.Arg119Leu missense_variant, splice_region_variant Exon 1 of 12 1 NM_170707.4 ENSP00000357283.4 P02545-1
LMNAENST00000677389.1 linkc.356G>T p.Arg119Leu missense_variant, splice_region_variant Exon 1 of 10 NM_005572.4 ENSP00000503633.1 P02545-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1
Nov 30, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine with leucine at codon 119 of the LMNA protein (p.Arg119Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LMNA-related conditions. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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. -

Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2 Uncertain:1
Oct 16, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
CardioboostCm
Uncertain
0.48
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
36
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
.;.;.;D;.
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;D
M_CAP
Pathogenic
0.68
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D
MetaSVM
Uncertain
0.70
D
MutationAssessor
Uncertain
2.8
M;.;M;M;M
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-3.9
D;D;D;D;D
REVEL
Pathogenic
0.85
Sift
Uncertain
0.012
D;D;D;D;D
Sift4G
Uncertain
0.028
D;D;D;D;D
Polyphen
1.0
D;.;D;D;.
Vest4
0.83
MutPred
0.68
Loss of MoRF binding (P = 0.0039);Loss of MoRF binding (P = 0.0039);Loss of MoRF binding (P = 0.0039);Loss of MoRF binding (P = 0.0039);Loss of MoRF binding (P = 0.0039);
MVP
0.93
MPC
2.2
ClinPred
0.99
D
GERP RS
4.0
RBP_binding_hub_radar
0.67
RBP_regulation_power_radar
3.5
Varity_R
0.85
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
0.42
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.42
Position offset: -32

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-156085065; API