chr1-156137756-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_005572.4(LMNA):​c.1711C>T​(p.Arg571Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 1,547,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R571H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

LMNA
NM_005572.4 missense

Scores

2
9
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9O:1

Conservation

PhyloP100: 3.30
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-156137756-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14485.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=1, Likely_pathogenic=2, not_provided=2}.
BP4
Computational evidence support a benign effect (MetaRNN=0.4197054).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LMNANM_005572.4 linkc.1711C>T p.Arg571Cys missense_variant Exon 10 of 10 ENST00000677389.1 NP_005563.1 P02545-2
LMNANM_170707.4 linkc.1698+13C>T intron_variant Intron 10 of 11 ENST00000368300.9 NP_733821.1 P02545-1A0A384MQX1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LMNAENST00000677389.1 linkc.1711C>T p.Arg571Cys missense_variant Exon 10 of 10 NM_005572.4 ENSP00000503633.1 P02545-2
LMNAENST00000368300.9 linkc.1698+13C>T intron_variant Intron 10 of 11 1 NM_170707.4 ENSP00000357283.4 P02545-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152186
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000466
AC:
7
AN:
150320
Hom.:
0
AF XY:
0.0000250
AC XY:
2
AN XY:
80064
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000122
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000696
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000401
AC:
56
AN:
1395630
Hom.:
0
Cov.:
32
AF XY:
0.0000363
AC XY:
25
AN XY:
688440
show subpopulations
Gnomad4 AFR exome
AF:
0.0000317
Gnomad4 AMR exome
AF:
0.000140
Gnomad4 ASJ exome
AF:
0.0000397
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000126
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000361
Gnomad4 OTH exome
AF:
0.000156
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152186
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000422
Hom.:
0
Bravo
AF:
0.0000416
ExAC
AF:
0.0000161
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2Other:1
-
Epithelial Biology; Institute of Medical Biology, Singapore
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jun 06, 2019
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 04, 2020
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Uncertain:1
-
Inherited Neuropathy Consortium
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Cardiomyopathy Uncertain:1
Apr 28, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant causes a C to T nucleotide substitution at the +13 position of intron 10 of the lamin A transcript (NM_170707.3). In the lamin C transcript (NM_005572.3), this variant corresponds to c.1711C>T, resulting in the missense variant (p.Arg571Cys) at the C-terminal end of the lamin C protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two related individuals affected with dilated cardiomyopathy (PMID: 31521807). This variant has also been reported in an individual affected with Emery-Dreifuss muscular dystrophy and peripheral neuropathy with no cardiac involvement, as well as in an unaffected parent (PMID: 15965218, 22326558). This variant has been identified in 7/150320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Charcot-Marie-Tooth disease type 2 Uncertain:1
Jul 08, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change falls in intron 10 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. This variant is present in population databases (rs80338938, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 15965218, 17377071, 22326558). This variant is also known as c.1711C>T (p.Arg571Cys). ClinVar contains an entry for this variant (Variation ID: 66611). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -

LMNA-related disorder Uncertain:1
Jul 26, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The LMNA c.1711C>T variant is predicted to result in the amino acid substitution p.Arg571Cys. This variant has been reported in multiple affected individuals in the literature, presenting with both cardiac and neurological phenotypes (Benedetti et al. 2005. PubMed ID: 15965218; Magagnotti. 2012. PubMed ID: 22326558). This variant is also reported in 0.012% of alleles in individuals of Latino descent in gnomAD, and has been listed in ClinVar as a variant of uncertain significance by multiple labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/66611/evidence/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Primary dilated cardiomyopathy Uncertain:1
Sep 18, 2024
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant causes a C to T nucleotide substitution at the +13 position of intron 10 of the lamin A transcript (NM_170707.3). In the lamin C transcript (NM_005572.3), this variant corresponds to c.1711C>T, resulting in the missense variant (p.Arg571Cys) at the C-terminal end of the lamin C protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two related individuals affected with dilated cardiomyopathy (PMID: 31521807). This variant has also been reported in an individual affected with Emery-Dreifuss muscular dystrophy and peripheral neuropathy with no cardiac involvement, as well as in an unaffected parent (PMID: 15965218, 22326558). This variant has been identified in 7/150320 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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
May 03, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1
Dec 06, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1698+13C>T intronic variant results from a C to T substitution 13 nucleotides after coding exon 10 in the LMNA gene. This alteration (also known as NM_005572.3:p.R571C, c.1711C>T) has been reported in individual(s) with features consistent with LMNA-related diseases including skeletal myopathy and dilated cardiomyopathy (Benedetti S et al. J Neurol Neurosurg Psychiatry, 2005 Jul;76:1019-21; Li Z et al. Heart Rhythm, 2020 02;17:305-312). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Pathogenic
0.23
CADD
Benign
21
DANN
Uncertain
1.0
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.73
T;T;T
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.42
T;T;T
MetaSVM
Uncertain
-0.072
T
PROVEAN
Benign
-0.34
N;.;N
REVEL
Uncertain
0.48
Sift
Pathogenic
0.0
D;.;D
Sift4G
Uncertain
0.038
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.34
MutPred
0.55
.;.;Loss of solvent accessibility (P = 3e-04);
MVP
0.88
ClinPred
0.18
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs80338938; hg19: chr1-156107547; API