rs56816490
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_170707.4(LMNA):c.949G>A(p.Glu317Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E317D) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )
Consequence
LMNA
NM_170707.4 missense
NM_170707.4 missense
Scores
13
5
2
Clinical Significance
Conservation
PhyloP100: 8.12
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 Pathogenic. Variant got 17 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, 10 uncertain in NM_170707.4
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.946
PP5
Variant 1-156135913-G-A is Pathogenic according to our data. Variant chr1-156135913-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156135913-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-156135913-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | c.949G>A | p.Glu317Lys | missense_variant | 6/12 | ENST00000368300.9 | NP_733821.1 | |
| LMNA | NM_005572.4 | c.949G>A | p.Glu317Lys | missense_variant | 6/10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | c.949G>A | p.Glu317Lys | missense_variant | 6/12 | 1 | NM_170707.4 | ENSP00000357283.4 | ||
| LMNA | ENST00000677389.1 | c.949G>A | p.Glu317Lys | missense_variant | 6/10 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000890 AC: 13AN: 1461384Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6AN XY: 726994
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GnomAD4 genome 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:17Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:7Other:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 07, 2021 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. This variant segregates with disease in at least one family. Computational tools predict that this variant is damaging. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 30, 2024 | 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: 27532257, 34768595, 18926329, 12898247, 11897440, 19318026, 28759816, 28679633, 30420677, 21846512, 31514951, 30287275, 32686758, 32160020, 34862408, 34616814, 34773379, 36291626, 25469153, 10939567, 24503780) - |
Dilated cardiomyopathy 1A Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Apr 22, 2022 | The c.949G>A variant has previously been reported in individuals with dilated cardiomyopathy [PMID: 34768595, 32686758, 32160020, 31514951, 21846512,27532257]. The variant has also been identified in multiple individuals with dilated cardiomyopathy with atrioventricular block [PMID: 11897440, 25469153]. Moreover, this variant has been shown to segregate with the isolated atrioventricular block in a large family [PMID: 25469153] and it has been deposited in ClinVar [ClinVar ID:48093] as Pathogenic and Likely Pathogenic by multiple submitters. The c.949G>A variant is observed in 4 alleles (0.00086% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.949G>A variant is located in exon 6 of this 12-exon gene and is predicted to replace an evolutionarily conserved glutamic acid amino acidwith lysine at position 317 in the coil 2B domain of the encoded protein. In silico predictions are in favor of damaging effect for (p.Glu317Lys) (CADD v1.6 = 34, REVEL =0.873); however, there are no functional studies to support or refute these predictions. Based on available evidence this c.949G>A (p.Glu317Lys) variant identified in LMNA is classified here as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 16, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Some missense variants have been reported to result in a toxic gain of function or dominant negative and are associated with childhood-onset disease or skeletal muscle involvement, while other variants have been reported to result in a loss of function and haploinsufficiency, and are associated with adult-onset disease, cardiac disorders or myopathy (PMID: 17377071). (I) 0108 - This gene is associated with both recessive and dominant disease. However, a clear genotype-phenotpe correlation associated with Emery-Dreifuss muscular dystrophy is yet to be established. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Glu317Asp): 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated coiled coil filament (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical diagnostic laboratories and has been identified in multiple individuals with DCM or suspected laminopathy (ClinVar, PMIDs: 21846512, 30287275, 34768595). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, no assertion criteria provided | clinical testing | Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University | Apr 27, 2021 | - - |
not specified Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 25, 2018 | The LMNA c.949G>A; p.Glu317Lys variant (rs56816490), is reported in the literature in multiple individuals and families affected with dilated cardiomyopathies (DCM) and atrioventricular block with DCM (Arbustini 2002, Millat 2009, Pasotti 2008, Villa 2014, Walsh 2017). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 48093) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamic acid at codon 317 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Glu317Lys variant is considered to be likely pathogenic. References: Arbustini E et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol. 2002 Mar 20;39(6):981-90. Millat G et al. Validation of high-resolution DNA melting analysis for mutation scanning of the LMNA gene. Clin Biochem. 2009 Jun;42(9):892-8. Pasotti M et al. Long-term outcome and risk stratification in dilated cardiolaminopathies. J Am Coll Cardiol. 2008 Oct 7;52(15):1250-60. Villa F et al. A G613A missense in the Hutchinson's progeria lamin A/C gene causes a lone, autosomal dominant atrioventricular block. Immun Ageing. 2014 Nov 26;11(1):19. Walsh R et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203. - |
Cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 27, 2016 | - - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 317 of the LMNA protein (p.Glu317Lys). This variant is present in population databases (rs56816490, gnomAD 0.007%). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 11897440, 21846512, 25469153, 27532257; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48093). 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%. For these reasons, this variant has been classified as Pathogenic. - |
LMNA-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 18, 2023 | The LMNA c.949G>A variant is predicted to result in the amino acid substitution p.Glu317Lys. This variant has been reported in multiple individuals with dilated cardiomyopathy or atrioventricular blockage and has also segregated within families (Table 1, Arbustini et al. 2002. PubMed ID: 11897440; Figure 1, Villa et al. 2014. PubMed ID: 25469153; Figure 2, Ferradini et al. 2021. PubMed ID: 34768595). This variant has been reported as a possible Italian founder variant (Ferradini et al. 2021. PubMed ID: 34768595). This variant is reported in 0.0065% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-156105704-G-A). This variant is interpreted as pathogenic for autosomal dominant LMNA-related disorders. - |
Primary familial dilated cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2023 | Variant summary: LMNA c.949G>A (p.Glu317Lys) results in a conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248396 control chromosomes (gnomAD). c.949G>A has been reported in the literature in multiple individuals and families affected with Dilated Cardiomyopathy (DCM) or DCM and atrioventricular block (AVB) or AVB alone; co-segregation with disease was documented within different families (e.g. Arbustini_2002, Pasotti_2008, Millat_2011, Villa_2014, Walsh_2017). The following publications have been ascertained in the context of this evaluation (PMID: 11897440, 21846512, 18926329, 25469153, 27532257). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Primary dilated cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 09, 2022 | The p.Glu317Lys variant in LMNA has been reported in at least 5 individuals with DCM and arrhythmia (atrioventricular (AV) block) and in 2 individuals with DCM and segregated with disease in at least 3 affected relatives from 3 families (Arbustini 2002 PMID: 11897440, Pasotti 2008 PMID: 18926329, Millat 2009 PMID: 19318026, Morales 2020 PMID: 32160020, LMM data). This variant has also been identified in 1 individual with AV block and a family history of sudden cardiac death (LMM data) and in a large family with isolated AV block, including one proband and 5 segregations (Villa 2014 PMID: 25469153). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 48093) and has also been identified in 0.001% (1/68028) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). Computational prediction tools and conservation analysis suggest that this variant may impact the protein. Variants in LMNA are prevalent in individuals with DCM and conduction system disease/arrhythmia and the presence of conduction system disease in the majority of affected individuals with this variant increases the likelihood that it is pathogenic. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PS4_Moderate, PP1_Moderate, PP3, PM2_Supporting. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 10, 2023 | The p.E317K pathogenic mutation (also known as c.949G>A), located in coding exon 6 of the LMNA gene, results from a G to A substitution at nucleotide position 949. The glutamic acid at codon 317 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in multiple individuals with dilated cardiomyopathy and/or atrioventricular block (AVB) or other arrhythmia, and has shown strong segregation with disease in a large Italian family with AVB (Arbustini E et al. J. Am. Coll. Cardiol. 2002;39:981-90; Pasotti M et al. J. Am. Coll. Cardiol. 2008;52:1250-60; Millat G et al. Eur J Med Genet. 2011;54:e570-5; Pugh TJ et al. Genet. Med. 2014;16:601-8; Villa F et al. Immun Ageing. 2014;11:19; Walsh R et al. Genet. Med., 2017 02;19:192-203; Captur G et al. Eur. J. Heart Fail., 2018 10;20:1413-1416; Kwapich M et al. Diabetes Metab., 2019 09;45:382-389; van Tienen FHJ et al. Eur. J. Hum. Genet., 2019 03;27:389-399). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;.;.;D;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M;M;M;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;T;D
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
P;.;P;D;.;.;P;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);Gain of MoRF binding (P = 0.0037);.;.;.;
MVP
MPC
2.2
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
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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