rs267607564
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_170707.4(LMNA):āc.1262T>Cā(p.Leu421Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L421L) has been classified as Likely benign.
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
6
4
10
Clinical Significance
Conservation
PhyloP100: 3.35
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;
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.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.1262T>C | p.Leu421Pro | missense_variant | 7/12 | ENST00000368300.9 | |
| LMNA | NM_005572.4 | c.1262T>C | p.Leu421Pro | missense_variant | 7/10 | ENST00000677389.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.1262T>C | p.Leu421Pro | missense_variant | 7/12 | 1 | NM_170707.4 | P1 | |
| LMNA | ENST00000677389.1 | c.1262T>C | p.Leu421Pro | missense_variant | 7/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152118Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
2
AN:
152118
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250794Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135646
GnomAD3 exomes
AF:
AC:
2
AN:
250794
Hom.:
AF XY:
AC XY:
1
AN XY:
135646
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1459986Hom.: 0 Cov.: 34 AF XY: 0.00000551 AC XY: 4AN XY: 726308
GnomAD4 exome
AF:
AC:
6
AN:
1459986
Hom.:
Cov.:
34
AF XY:
AC XY:
4
AN XY:
726308
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.0000131 AC: 2AN: 152118Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74294
GnomAD4 genome
AF:
AC:
2
AN:
152118
Hom.:
Cov.:
33
AF XY:
AC XY:
1
AN XY:
74294
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ExAC
AF:
AC:
1
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:6Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1Other:1
| not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 23, 2023 | Identified in a patient with obesity, diabetes, hypertension, left ventricular hypertrophy, and muscle pain and weakness in published literature (Decaudain et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional assays have contradictory findings on the effect of p.(L421P) on lamin A nucleus import in cell lines (Yang et al., 2013; Kiel et al., 2014), and suggest impairment of morphological and physiological features in patient cells, although quantitative analysis of lamin A expression was not described (Caron et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23977161, 24943589, 17711925, 32376792, 23853504, 17612587, 36354755, 10939567) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 29, 2021 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2022 | Variant summary: LMNA c.1262T>C (p.Leu421Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250794 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1262T>C has been reported in the literature in individuals with LMNA-Related Disorders (examples: Caron_2007, Decaudain_2007, Carboni_2013, Lin_2020, and Volodarsky_2021). However, these reports do not provide unequivocal conclusions about association of the variant with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant had nuclear shape abnormalities, reduced proliferative activity, increased mitochondrial alterations, increased oxidative stress and premature cellular senescence (Caron_2007). Additional studies reported the variant does not impair trafficking of the protein (Decaudain_2007) and does not alter distribution of Nesprin-2 but shows reduced Nesprin-2 binding (Yang_2013). Furthermore, Kiel et al (2014) determined the variant has significantly reduced nuclear accumulation and exhibits altered subcellular localization and reduced lamina incorporation. However, this data does not allow convincing conclusions about the variant effect and how it relates to onset of laminopathies clinically. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence of clinical importance becomes available. - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 19, 2023 | This missense variant replaces leucine with proline at codon 421 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant causes accumulation of prelamin A and nuclear shape abnormalities (PMID: 17612587) and impacts the interaction with nesprin-2 (PMID: 23977161). However, clinical relevance of these observations is not clear. This variant has been reported in an individual affected with severe metabolic syndrome (PMID: 17711925), in an individual with laminopathy with musculoskeletal and metabolic phenotype (PMID: 23853504), in an individual with laminopathy with cardiac and metabolic phenotype (PMID: 23853504), and in an individual with suspected Charcot-Marie-Tooth (PMID: 32376792). This variant has been identified in 3/282158 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
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 09, 2022 | Experimental studies have shown that this missense change affects LMNA function (PMID: 17612587, 23977161, 24943589). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 66798). This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 17711925, 32376792). This variant is present in population databases (rs267607564, gnomAD 0.002%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 421 of the LMNA protein (p.Leu421Pro). 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. - |
Primary dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 02, 2023 | This missense variant replaces leucine with proline at codon 421 of the lamin A/C proteins. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant causes accumulation of prelamin A and nuclear shape abnormalities (PMID: 17612587) and impacts the interaction with nesprin-2 (PMID: 23977161). However, clinical relevance of these observations is not clear. This variant has been reported in an individual affected with severe metabolic syndrome (PMID: 17711925), in an individual with laminopathy with musculoskeletal and metabolic phenotype (PMID: 23853504), in an individual with laminopathy with cardiac and metabolic phenotype (PMID: 23853504), and in an individual with suspected Charcot-Marie-Tooth (PMID: 32376792). This variant has been identified in 3/282158 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. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 21, 2017 | The p.L421P variant (also known as c.1262T>C), located in coding exon 7 of the LMNA gene, results from a T to C substitution at nucleotide position 1262. The leucine at codon 421 is replaced by proline, an amino acid with similar properties. This alteration was detected in an individual from a metabolic syndrome cohort with central obesity, diabetes, hypertension and left ventricular hypertrophy (Decaudain A et al. J Clin Endocrinol Metab. 2007;92:4835-44). Limited functional studies have suggested this variant may result in mild defects in lamin A intranuclear localization (Decaudain A et al. J Clin Endocrinol Metab. 2007;92:4835-44; Yang L et al. PLoS ONE. 2013;8:e71850; Kiel T et al. Int J Biochem Cell Biol. 2014;53:271-80). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
DEOGEN2
Pathogenic
.;.;.;D;.;.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T;T;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L;L;L;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Benign
T;T;T;T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
B;.;B;B;.;.;B;.;.
Vest4
MutPred
Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);.;.;.;.;
MVP
MPC
0.57
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at