rs878855233
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2
The NM_170707.4(LMNA):c.1517A>C(p.His506Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000533 in 1,613,488 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. H506D) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000056 ( 0 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
5
6
8
Clinical Significance
Conservation
PhyloP100: 5.19
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 7 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr1-156137140-C-G is described in Lovd as [Pathogenic].
PP2
?
Missense variant where missense usually causes diseases, LMNA
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.1517A>C | p.His506Pro | missense_variant | 9/12 | ENST00000368300.9 | |
| LMNA | NM_005572.4 | c.1517A>C | p.His506Pro | missense_variant | 9/10 | ENST00000677389.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.1517A>C | p.His506Pro | missense_variant | 9/12 | 1 | NM_170707.4 | P1 | |
| LMNA | ENST00000677389.1 | c.1517A>C | p.His506Pro | missense_variant | 9/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000281 AC: 7AN: 248754Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134742
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:20
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 20, 2021 | The p.His506Pro variant in LMNA has been reported in 4 individuals with DCM, 1 individual with HCM, 1 individual with cardiac conduction defects, 1 individual with cystic kidney disease, and 1 individual with familial partial lipodystrophy (Angori 2017 PMID: 28531892, Jansweijer 2017 PMID: 27813223, Robyns 2017 PMID: 29255176, Ditaranto 2019 PMID: 31744510, Dron 2020 PMID: 32041611, Park 2020 PMID: 31383942, Verdonschot 2020 PMID: 32880476, Visser 2016). It has also been identified in 0.005% (7/127728) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant impacts protein function (Angori 2017 PMID: 28531892, Bernasconi 2018 PMID: 29693488, Mattioli 2018 PMID: 30326651); however, these types of assays may not accurately represent biological function. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Supporting. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 04, 2015 | The H506P variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The H506P variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H506P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in most mammals, however Proline is the wild type residue at this position in platypus and Alanine is present at this position in alpaca. Missense mutations in this residue (H506D) and nearby residues (W498R, W498C, L512P) have been reported in the Human Gene Mutation Database in association with metabolic laminopathy, muscular dystrophy and myopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | LMNA: PM1, PM2:Supporting, PS4:Supporting - |
Emery-Dreifuss muscular dystrophy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 06, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 22, 2023 | This missense variant replaces histidine with proline at codon 506 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental studies have shown that this variant impacts the interaction with Ankrd2 (PMID: 28531892) and Samp1 (PMID: 30326651), leading to altered subcellular localization of these proteins. This variant has been reported in an individual affected with dilated cardiomyopathy (DOI:10.1093/europace/18.suppl_1.i167a), in an individual affected with hypertrophic cardiomyopathy (PMID: 29255176), in an individual affected with Emery-Dreifuss Muscular Dystrophy (PMID: 28531892), and in an individual affected with laminopathy in the absence of neuromuscular involvement (PMID: 31744510). This variant has been identified in 9/280138 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 2B1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 06, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Congenital muscular dystrophy due to LMNA mutation Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 06, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Dilated cardiomyopathy 1A Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 06, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Hypertrophic cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Apr 30, 2017 | - - |
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
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 23, 2022 | - - |
Hutchinson-Gilford syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 06, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 12, 2022 | Variant summary: LMNA c.1517A>C (p.His506Pro) results in a non-conservative amino acid change located in the Lamin tail domain (IPR001322) of 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 2.8e-05 in 248754 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1517A>C has been reported in the literature in individuals affected with Dilated Cardiomyopathy (example, Jansweijer_2017, Hoorntje_2017, Verdonschot_2020). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function reporting an altered interaction between prelamin A and Ankrd2 resulting in mislocalization of Ankrd2 in the nucleus (example, Angori_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Mandibuloacral dysplasia with type A lipodystrophy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 06, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Charcot-Marie-Tooth disease type 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 506 of the LMNA protein (p.His506Pro). This variant is present in population databases (no rsID available, gnomAD 0.005%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27813223). ClinVar contains an entry for this variant (Variation ID: 242003). 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%. 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. - |
Lethal tight skin contracture syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 06, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Lipoatrophy with Diabetes, Hepatic Steatosis, Hypertrophic Cardiomyopathy, and Leukomelanodermic Papules Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 06, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Familial partial lipodystrophy, Dunnigan type Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 06, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Primary dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This missense variant replaces histidine with proline at codon 506 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental studies have shown that this variant impacts the interaction with Ankrd2 (PMID: 28531892) and Samp1 (PMID: 30326651), leading to altered subcellular localization of these proteins. This variant has been reported in an individual affected with dilated cardiomyopathy (Visser et al. 2016, DOI: 10.1093/europace/18.suppl_1.i167a), in an individual affected with hypertrophic cardiomyopathy (PMID: 29255176), in an individual affected with Emery-Dreifuss Muscular Dystrophy (PMID: 28531892), and in an individual affected with a laminopathy absence of neuromuscular involvement (PMID: 31744510). This variant has been identified in 9/280138 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 | Jul 16, 2021 | The p.H506P variant (also known as c.1517A>C), located in coding exon 9 of the LMNA gene, results from an A to C substitution at nucleotide position 1517. The histidine at codon 506 is replaced by proline, an amino acid with similar properties. This alteration has been reported in one participant from a dilated cardiomyopathy (DCM) cohort (Jansweijer JA et al. Eur. J. Heart Fail., 2017 04;19:512-521), and, although details were limited, in an individual with Emery-Dreifuss muscular dystrophy 2 (EDMD2) (Angori S et al. Cell. Physiol. Biochem., 2017 May;42:169-184). Functional studies have suggested that p.H506P alters localization of Ankrd2 and Samp1 proteins in muscle cells, while a study of fibroblasts and myoblasts derived from an EDMD2 patient heterozygous for p.H506P revealed increased TGF-beta2 serum levels; however, the physiological relevance of these results is unclear (Angori S et al. Cell. Physiol. Biochem., 2017 May;42:169-184; Mattioli E et al. Cells, 2018 Oct;7; Bernasconi P et al. Nucleus, 2018 Jan;9:292-304). This amino acid position is well conserved in available vertebrate species; however, proline is the reference amino acid in other 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. - |
Emery-Dreifuss muscular dystrophy 2, autosomal dominant Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 06, 2019 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;T;D;D;D;D;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
M;M;M;M;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Benign
T;D;D;T;D;T;D;D
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
B;B;B;.;.;B;.;.
Vest4
MutPred
Gain of glycosylation at H506 (P = 0.0153);Gain of glycosylation at H506 (P = 0.0153);Gain of glycosylation at H506 (P = 0.0153);Gain of glycosylation at H506 (P = 0.0153);.;.;.;.;
MVP
MPC
0.55
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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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