chr1-156135260-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_170707.4(LMNA):​c.884C>T​(p.Ser295Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,512 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S295P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

LMNA
NM_170707.4 missense

Scores

1
12
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 2.72

Publications

5 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: Uncertain_significance. The variant received 2 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_170707.4

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LMNANM_170707.4 linkc.884C>T p.Ser295Leu missense_variant Exon 5 of 12 ENST00000368300.9 NP_733821.1 P02545-1A0A384MQX1
LMNANM_005572.4 linkc.884C>T p.Ser295Leu missense_variant Exon 5 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.884C>T p.Ser295Leu missense_variant Exon 5 of 12 1 NM_170707.4 ENSP00000357283.4 P02545-1
LMNAENST00000677389.1 linkc.884C>T p.Ser295Leu missense_variant Exon 5 of 10 NM_005572.4 ENSP00000503633.1 P02545-2

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152256
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:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000239
AC:
6
AN:
250592
AF XY:
0.0000369
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.000164
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461256
Hom.:
0
Cov.:
34
AF XY:
0.0000165
AC XY:
12
AN XY:
726934
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.0000447
AC:
2
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86232
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52846
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000126
AC:
14
AN:
1111990
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152256
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74384
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41472
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5206
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.0000441
AC:
3
AN:
68046
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.438
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:5
Jan 25, 2022
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Oct 13, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 28, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Reported previously as a variant of uncertain significance in a parent whose child had a diagnosis of heterotaxy; however, no further clinical information was provided on the parent and it was unclear if the child also harbored the variant (Chetruengchai and Shotelersuk, 2022); Reported previously in an individual diagnosed with HCM; however, further clinical, family history, and segregation details were unavailable (Lopes et al., 2015); Reported previously as a variant of uncertain significance in a patient with non-ischemic cardiomyopathy and previous heart transplantation; however, further clinical and segregation information was provided (Boen et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28663758, 10939567, 34621001, 35581137, 25351510) -

-
Clinical Genetics, Academic Medical Center
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Primary dilated cardiomyopathy Uncertain:2
Oct 27, 2023
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces serine with leucine at codon 295 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30847666), in an individual affected with unspecified cardiomyopathy (PMID: 35581137), and in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 7/281984 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. -

Feb 26, 2021
Loeys Lab, Universiteit Antwerpen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change results in a missense variant in the LMNA gene (p.(Ser295Leu)) (PP2; based on GnomAd constraint matrix). The variant is described in LVOD as variant of unknown significance (LMNA_000421). This variant is present in GnomAD with a prevalence of 7/276586.This variant has been described in literature in an individual with HCM (PMID: 25351510) but was also seen in a control-population (PMID: 28663758) .The variant affects a weakly conserved nucleotide and a moderately conserved amino acid. Prediction programs classify the variant as benign (Align GVGD: C0; Polyphen-2-HumDiv: benign ; Polyphen-2-HumVar: benign; SIFT: tolerated; MutationTaster: no result) (BP4). It is located in the intermediate filament rod domain of the LMNA protein. Functional assays have not been performed for this variant. We identified this variant in a 2 unrelated patients with DCM and a third unrelated patient presenting with refractory Ventricular tachycardia in absence of structural cardiac abnormalities. No data on segregation were available. In conclusion this variant was classified as variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met: BS4, PP2). -

Cardiomyopathy Uncertain:1
Jul 06, 2023
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces serine with leucine at codon 295 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30847666), in an individual affected with unspecified cardiomyopathy (PMID: 35581137), and in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 7/281984 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
Nov 21, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 295 of the LMNA protein (p.Ser295Leu). This variant is present in population databases (rs769210828, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 20848652, 30847666, 34621001; internal data). ClinVar contains an entry for this variant (Variation ID: 518983). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect LMNA function (PMID: 34862408). 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. -

Cardiovascular phenotype Uncertain:1
Mar 01, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.S295L variant (also known as c.884C>T), located in coding exon 5 of the LMNA gene, results from a C to T substitution at nucleotide position 884. The serine at codon 295 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort and dilated cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Boen HM et al. J Heart Lung Transplant, 2022 Sep;41:1218-1227). This variant was detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This alteration has also been reported as a secondary finding in an exome cohort (Chetruengchai W et al. J Hum Genet, 2022 Mar;67:137-142). Another alteration affecting this amino acid (p.S295P, c.883T>C) has been reported in a single individual with muscular dystrophy and cardiomyopathy with conduction disease (Scharner J et al. Hum. Mutat., 2011 Feb;32:152-67). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
CardioboostCm
Benign
0.034
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
0.030
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
.;.;.;D;.;.;.;.
Eigen
Benign
-0.071
Eigen_PC
Benign
0.089
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Uncertain
0.59
D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.31
T
MutationAssessor
Benign
0.41
N;.;N;N;N;.;.;.
PhyloP100
2.7
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-2.8
D;D;D;D;D;D;D;D
REVEL
Uncertain
0.44
Sift
Uncertain
0.010
D;D;T;T;T;T;T;T
Sift4G
Benign
0.77
T;T;T;T;T;T;T;T
Polyphen
0.014
B;.;B;B;.;.;B;.
Vest4
0.60
MutPred
0.52
Loss of phosphorylation at S295 (P = 0.0206);Loss of phosphorylation at S295 (P = 0.0206);Loss of phosphorylation at S295 (P = 0.0206);Loss of phosphorylation at S295 (P = 0.0206);Loss of phosphorylation at S295 (P = 0.0206);.;.;.;
MVP
0.96
MPC
0.88
ClinPred
0.37
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.10
gMVP
0.91
Mutation Taster
=47/53
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: rs769210828; hg19: chr1-156105051; API