chr1-156134518-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_170707.4(LMNA):​c.629T>G​(p.Ile210Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. I210N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

LMNA
NM_170707.4 missense

Scores

8
11
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2O:1

Conservation

PhyloP100: 6.23

Publications

7 publications found
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]
LMNA Gene-Disease associations (from GenCC):
  • dilated cardiomyopathy
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • dilated cardiomyopathy 1A
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
  • familial partial lipodystrophy, Dunnigan type
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
  • Hutchinson-Gilford progeria syndrome
    Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • restrictive dermopathy 2
    Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
  • Emery-Dreifuss muscular dystrophy 2, autosomal dominant
    Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
  • atrioventricular block
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • heart-hand syndrome, Slovenian type
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
  • Charcot-Marie-Tooth disease type 2B1
    Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
  • Emery-Dreifuss muscular dystrophy 3, autosomal recessive
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • mandibuloacral dysplasia with type A lipodystrophy
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
  • atrial fibrillation
    Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
  • atypical Werner syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal dominant Emery-Dreifuss muscular dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • congenital muscular dystrophy due to LMNA mutation
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • lethal restrictive dermopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • LMNA-related cardiocutaneous progeria syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal recessive Emery-Dreifuss muscular dystrophy
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal semi-dominant severe lipodystrophic laminopathy
    Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet
  • arrhythmogenic right ventricular cardiomyopathy
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 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, 10 uncertain in NM_170707.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.898
PP5
Variant 1-156134518-T-G is Pathogenic according to our data. Variant chr1-156134518-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48072.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LMNANM_170707.4 linkc.629T>G p.Ile210Ser missense_variant Exon 3 of 12 ENST00000368300.9 NP_733821.1 P02545-1A0A384MQX1
LMNANM_005572.4 linkc.629T>G p.Ile210Ser missense_variant Exon 3 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.629T>G p.Ile210Ser missense_variant Exon 3 of 12 1 NM_170707.4 ENSP00000357283.4 P02545-1
LMNAENST00000677389.1 linkc.629T>G p.Ile210Ser missense_variant Exon 3 of 10 NM_005572.4 ENSP00000503633.1 P02545-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1Uncertain:1
Oct 30, 2024
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PM2, PS3_supp, PS4_supp, PP2, PP3 -

Jan 14, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.I210S variant (also known as c.629T>G), located in coding exon 3 of the LMNA gene, results from a T to G substitution at nucleotide position 629. The isoleucine at codon 210 is replaced by serine, an amino acid with dissimilar properties. This variant was reported in individual(s) with features consistent with LMNA-related laminopathy (Parks SB et al. Am Heart J, 2008 Jul;156:161-9; Castrini AI et al. J Am Heart Assoc, 2022 Apr;11:e024960). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified Uncertain:1
Nov 01, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Ile210Ser v ariant in LMNA has been reported in 1 individual with DCM and AFib (Parks 2008) and identified by our laboratory in 1 individual with DCM. In addition, function al studies have shown that this variant impacts protein function (Cowan 2010). H owever, this in vitro assay may not accurately represent biological function. Th is variant was absent from large population studies. Computational analyses (bio chemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) su ggest that this variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, while the presence in a ffected individuals, functional studies, and low frequency all suggest that the Ile210Ser variant may be pathogenic, additional studies are needed to fully asse ss its clinical significance. -

not provided Other:1
-
Epithelial Biology; Institute of Medical Biology, Singapore
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
CardioboostCm
Uncertain
0.54
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.95
.;.;.;D;.;.;.;D;.
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.97
D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.65
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.59
D
MutationAssessor
Uncertain
2.3
M;.;M;M;M;.;.;.;.
PhyloP100
6.2
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-4.3
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0010
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;D;D;D;D;D;D
Polyphen
0.86
P;.;D;P;.;.;D;.;.
Vest4
0.85
MutPred
0.73
Loss of catalytic residue at I210 (P = 0.0053);Loss of catalytic residue at I210 (P = 0.0053);Loss of catalytic residue at I210 (P = 0.0053);Loss of catalytic residue at I210 (P = 0.0053);Loss of catalytic residue at I210 (P = 0.0053);.;.;.;.;
MVP
0.99
MPC
2.4
ClinPred
0.99
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.88
gMVP
0.96
Mutation Taster
=0/100
disease causing

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

Other links and lift over

dbSNP: rs267607572; hg19: chr1-156104309; API