rs28928902

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5

The NM_170707.4(LMNA):ā€‹c.1411C>Gā€‹(p.Arg471Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,144 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. R471P) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)

Consequence

LMNA
NM_170707.4 missense

Scores

12
7
1

Clinical Significance

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

Conservation

PhyloP100: 0.752
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr1-156136951-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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, 0.991
PP5
Variant 1-156136951-C-G is Pathogenic according to our data. Variant chr1-156136951-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 66824.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=2, Uncertain_significance=1}. Variant chr1-156136951-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LMNANM_170707.4 linkuse as main transcriptc.1411C>G p.Arg471Gly missense_variant 8/12 ENST00000368300.9
LMNANM_005572.4 linkuse as main transcriptc.1411C>G p.Arg471Gly missense_variant 8/10 ENST00000677389.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LMNAENST00000368300.9 linkuse as main transcriptc.1411C>G p.Arg471Gly missense_variant 8/121 NM_170707.4 P1P02545-1
LMNAENST00000677389.1 linkuse as main transcriptc.1411C>G p.Arg471Gly missense_variant 8/10 NM_005572.4 P02545-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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
GnomAD4 exome
Cov.:
32
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152144
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00
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
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not provided Uncertain:1Other:1
not provided, no classification providedliterature onlyEpithelial Biology; Institute of Medical Biology, Singapore-- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicOct 18, 2022PP3, PM2_supporting -
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingInvitaeJul 08, 2022Advanced 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg471 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18646565, 23582089, 27532257, 29943882). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 66824). This missense change has been observed in individual(s) with clinical features of autosomal dominant lipodystrophy (PMID: 18041775). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 471 of the LMNA protein (p.Arg471Gly). -
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 13, 2022The p.R471G variant (also known as c.1411C>G), located in coding exon 8 of the LMNA gene, results from a C to G substitution at nucleotide position 1411. The arginine at codon 471 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in an individual with dilated cardiomyopathy (DCM) and cardiac conduction disease, as well as in two siblings with familial partial lipodystrophy (Muschke P et al. Am. J. Med. Genet. A, 2007 Dec;143A:2810-4; Ambry internal data). Another alteration at the same codon, p.R471H (c.1412G>A), has been reported in association with laminopathy and DCM (Astejada MN et al. Acta Myol. 2007; 26(3):159-64). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
CardioboostCm
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
.;.;D;.;.;.;.;D
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.87
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.83
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H;H;H;H;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-6.3
D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.92
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
0.95
MutPred
0.95
Loss of methylation at K470 (P = 0.0624);Loss of methylation at K470 (P = 0.0624);Loss of methylation at K470 (P = 0.0624);Loss of methylation at K470 (P = 0.0624);.;.;.;.;
MVP
0.98
MPC
1.3
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.99
gMVP
0.96

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28928902; hg19: chr1-156106742; API