rs57520892
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP5
The NM_170707.4(LMNA):c.1580G>A(p.Arg527His) variant causes a missense change. The variant allele was found at a frequency of 0.0000257 in 1,598,282 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R527C) has been classified as Likely pathogenic.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
4
10
5
Clinical Significance
Conservation
PhyloP100: 5.39
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 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, 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 chr1-156137204-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 14481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, LMNA
PP5
?
Variant 1-156137204-G-A is Pathogenic according to our data. Variant chr1-156137204-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 14499.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Uncertain_significance=3, not_provided=1}. Variant chr1-156137204-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.1580G>A | p.Arg527His | missense_variant | 9/12 | ENST00000368300.9 | |
| LMNA | NM_005572.4 | c.1580G>A | p.Arg527His | missense_variant | 9/10 | ENST00000677389.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.1580G>A | p.Arg527His | missense_variant | 9/12 | 1 | NM_170707.4 | P1 | |
| LMNA | ENST00000677389.1 | c.1580G>A | p.Arg527His | missense_variant | 9/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152216Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000410 AC: 9AN: 219426Hom.: 0 AF XY: 0.0000168 AC XY: 2AN XY: 119110
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:9Uncertain:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:3Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 28, 2020 | - - |
| not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 19, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 2021 | Published functional studies demonstrate a damaging effect: failure to restore p16ink4A/pRB pathway signaling, increased sensitivity to ionizing radiation, and destabilization of heterochromatin-associated proteins (Filesi et al., 2005; Nitta et al., 2006; di Masi et al., 2008); 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: 23891399, 24375749, 25637381, 18604166, 12075506, 14627682, 12788894, 16046620, 19764019, 28663758, 25823658, 19084400, 17848409, 31589614, 32041611, 32376792, 34135346, 33422685, 10939567, 33038109, 15473259, 29854317, 25324471, 16809772, 10080180, 31383942) - |
Mandibuloacral dysplasia with type A lipodystrophy Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2009 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 09, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Mandibuloacral dysplasia Pathogenic:1Uncertain:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 08, 2019 | The p.Arg527His variant in LMNA has been reported in the homozygous or compound heterozygous state in 10 individuals with mandiculoacral dysplasia (MAD) and segregated with disease in 5 affected individuals from 4 families (Novelli 2002, Shen 2003, Simha 2003, Garavelli 2009). It has also been identified in 6/31826 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org), however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 14499). In vitro functional studies support an impact on protein function (Novelli 2002, Amati 2004, Filesi 2005, Nitta 2006, Lombardi 2007, Meaburn 2007, di Masi 2008, Evangelisti 2015). Three additional variants involving this codon (p.Arg527) have been identified in individuals with MAD (Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MAD. ACMG/AMP Criteria applied: PM3_VeryStrong, PS4, PM5_Strong, PP1_Strong, PS3_Moderate, BP4. - |
| Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Charcot-Marie-Tooth disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Mandibuloacral dysplasia with type A lipodystrophy, atypical Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2009 | - - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 527 of the LMNA protein (p.Arg527His). This variant is present in population databases (rs57520892, gnomAD 0.02%). This missense change has been observed in individuals with autosomal recessive mandibuloacral dysplasia (PMID: 12075506, 14627682). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14499). Advanced 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LMNA function (PMID: 12075506, 18604166, 25324471, 25823658). For these reasons, this variant has been classified as Pathogenic. - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 16, 2023 | This missense variant replaces arginine with histidine at codon 527 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). In a transgenic mouse model, this variant has been associated with phenotypes relevant for mandibuloacral dysplasia type A syndrome while muscle phenotypes are normal (PMID: 33458588). Fibroblast cell cultures from the transgenic mice displayed nuclear envelope aberrations, accumulation of the lamin A precursor protein, proliferation, and senescence rate defects (PMID: 33458588). Another functional study has shown that cells from a homozygous carrier show abnormal nuclear morphology, while cells from a heterozygous carrier show normal nuclear morphology (PMID: 12075506). Other functional studies have suggested that this variant may increase sensitivity to ionizing radiation (PMID:18604166), affect DNA synthesis (PMID 25324471) and fail to downregulate TGFbeta-2 secretion (PMID: 25823658). This variant has been associated with autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease in several families and has been reported in the homozygous or compound heterozygous states in multiple affected individuals (PMID: 12075506, 14627682, 25286833, 32376792, 33038109, 33422685, 34680903, Xu et al. 2019 doi: 10.3969/j.issn.1000-3606.2019.09.010). Most affected carriers showed no signs of cardiac involvement except for one individual who was also affected with dilated cardiomyopathy (PMID: 33422685). Heterozygous parents were reported to be healthy. This variant has also been identified in 10/250812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease (ClinVar variation ID: 14499). - |
Primary dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces arginine with histidine at codon 527 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). In a transgenic mouse model, this variant has been associated with phenotypes relevant for mandibuloacral dysplasia type A syndrome while muscle phenotypes are normal (PMID: 33458588). Fibroblast cell cultures from the transgenic mice displayed nuclear envelope aberrations, accumulation of the lamin A precursor protein, proliferation, and senescence rate defects (PMID: 33458588). Another functional study has shown that cells from a homozygous carrier show abnormal nuclear morphology, while cells from a heterozygous carrier show normal nuclear morphology (PMID: 12075506). Other functional studies have suggested that this variant may increase sensitivity to ionizing radiation (PMID:18604166), affect DNA synthesis (PMID 25324471) and fail to downregulate TGFbeta-2 secretion (PMID: 25823658). This variant has been associated with autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease in several families and has been reported in the homozygous or compound heterozygous states in multiple affected individuals (PMID: 12075506, 14627682, 25286833, 32376792, 33038109, 33422685, 34680903, Xu et al. 2019 doi: 10.3969/j.issn.1000-3606.2019.09.010). Most affected carriers showed no signs of cardiac involvement except for one individual who was also affected with dilated cardiomyopathy (PMID: 33422685). Heterozygous parents were reported to be healthy. This variant has also been identified in 10/250812 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant cardiomyopathy, although it is known to cause autosomal recessive mandibuloacral dysplasia and Charcot-Marie-Tooth disease (ClinVar variation ID: 14499). - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2021 | The p.R527H variant (also known as c.1580G>A), located in coding exon 9 of the LMNA gene, results from a G to A substitution at nucleotide position 1580. The arginine at codon 527 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in several homozygous individuals with autosomal recessive mandibuloacral dysplasia (MAD) (Shen JJ et al. J. Med. Genet., 2003 Nov;40:854-7; Garavelli L et al. Am. J. Med. Genet. A, 2009 Oct;149A:2258-64; Sakka et al. Eur J Med Genet, 2021 Feb;64:104138; Jéru I et al. Genes (Basel), 2021 Sep;12:[Epub ahead of print]). Compound heterozygosity (p.R527H/p.V440M) has also been reported in an individual with overlapping MAD and laminopathy features that were considered atypical along with a limb-girdle-like myopathy (Lombardi F et al. J. Clin. Endocrinol. Metab., 2007 Nov;92:4467-71). Heterozygous carrier family members and healthy population cohort participants have been reported to be unaffected with MAD or other laminopathy-related phenotypes (Dron JS et al. BMC Med Genomics, 2020 02;13:23; Lacaze P et al. NPJ Genom Med, 2021 Jun;6:51; Sakka et al. Eur J Med Genet, 2021 Feb;64:104138). Functional studies demonstrate that lamin A plays an important role in TGFbeta 2 regulation and that this alteration affects genomic stability and DNA damage response with the accumulation of lamin A precursor protein after X-ray exposure (Novelli G et al. Am. J. Hum. Genet., 2002 Aug;71:426-31; Evangelisti C et al. Oncotarget, 2015 Apr;6:7424-37; di Masi A et al. Cell Cycle, 2008 Jul;7:2030-7). 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 supporting evidence, this variant is expected to be causative of mandibuloacral dysplasia (MAD) when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant laminopathy-related phenotypes is unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
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
REVEL
Pathogenic
Sift
Benign
D;.;D;D;D;D;D;D;D
Sift4G
Benign
T;T;T;T;T;T;T;T;T
Polyphen
B;.;B;B;.;.;B;.;.
Vest4
MVP
MPC
0.44
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at