rs56816490
Variant summary
Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PP3_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. E317G) has been classified as Uncertain significance.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
Publications
- dilated cardiomyopathyInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- dilated cardiomyopathy 1AInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet
- familial partial lipodystrophy, Dunnigan typeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
- Hutchinson-Gilford progeria syndromeInheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- restrictive dermopathy 2Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: G2P
- Emery-Dreifuss muscular dystrophy 2, autosomal dominantInheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
- atrioventricular blockInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- heart-hand syndrome, Slovenian typeInheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
- Charcot-Marie-Tooth disease type 2B1Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
- Emery-Dreifuss muscular dystrophy 3, autosomal recessiveInheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- mandibuloacral dysplasia with type A lipodystrophyInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
- atrial fibrillationInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- atypical Werner syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- autosomal dominant Emery-Dreifuss muscular dystrophyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- congenital muscular dystrophy due to LMNA mutationInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- lethal restrictive dermopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- LMNA-related cardiocutaneous progeria syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- autosomal recessive Emery-Dreifuss muscular dystrophyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathy-hypergonadotropic hypogonadism syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- autosomal semi-dominant severe lipodystrophic laminopathyInheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet
- arrhythmogenic right ventricular cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 14 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_170707.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LMNA | NM_170707.4 | MANE Select | c.949G>A | p.Glu317Lys | missense | Exon 6 of 12 | NP_733821.1 | ||
| LMNA | NM_005572.4 | MANE Plus Clinical | c.949G>A | p.Glu317Lys | missense | Exon 6 of 10 | NP_005563.1 | ||
| LMNA | NM_001406985.1 | c.949G>A | p.Glu317Lys | missense | Exon 6 of 13 | NP_001393914.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LMNA | ENST00000368300.9 | TSL:1 MANE Select | c.949G>A | p.Glu317Lys | missense | Exon 6 of 12 | ENSP00000357283.4 | ||
| LMNA | ENST00000677389.1 | MANE Plus Clinical | c.949G>A | p.Glu317Lys | missense | Exon 6 of 10 | ENSP00000503633.1 | ||
| LMNA | ENST00000368299.7 | TSL:1 | c.949G>A | p.Glu317Lys | missense | Exon 6 of 12 | ENSP00000357282.3 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1461384Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6AN XY: 726994 show subpopulations
Age Distribution
GnomAD4 genome 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
ClinVar
Submissions by phenotype
not provided Pathogenic:7Other:1
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, 36396199, 21846512, 31514951, 30287275, 32686758, 32160020, 34862408, 34616814, 34773379, 36291626, 25469153, 24503780, 36264615, 39204134, 10939567, 40359255, 39923945, 37652022, 38837338, 38979608)
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.
Dilated cardiomyopathy 1A Pathogenic:3
The LMNA c.949G>A (p.Glu317Lys) variant has been reported in more than five individuals affected with dilated cardiomyopathy (Ferradini V et al., PMID: 34768595; Millat G et al., PMID: 21846512; Ormondroyd E et al., PMID: 3268675; Pasotti M et al., PMID: 18926329; Walsh R et al., PMID: 27532257), in six individuals affected with both dilated cardiomyopathy and arrhythmia caused by atrioventricular (AV) block (Arbustini E et al., PMID: 11897440; Verga L et al., PMID: 12898247; Millat G et al., PMID: 19318026; Villa F et al., PMID: 25469153; Santobuono VE et al., PMID: 34616814; Gerbino A et al., PMID: 34773379), and is reported to segregate with disease in at least 3 affected relatives from 4 families (Arbustini E et al., PMID: 11897440; Ferradini V et al., PMID: 34768595; Pasotti M et al., PMID: 18926329; Villa F et al., PMID: 25469153). This variant has been reported in the ClinVar database as a pathogenic variant by ten submitters and as a likely pathogenic variant by seven submitters (Variation ID: 48093). This variant is only observed on 1 out of 31,394 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact on LMNA function. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.
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.
Primary dilated cardiomyopathy Pathogenic:2
This sequence change in LMNA is predicted to replace glutamic acid with lysine at codon 317, p.(Glu317Lys). The glutamic acid residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the IF rod domain. There is a small physicochemical difference between glutamic acid and lysine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.001% (14/1,179,932 alleles) in the European (non-Finnish) population, which is consistent with dilated cardiomyopathy. This variant has been reported in multiple individuals with phenotypes consistent with laminopathy (mainly cardiac conditions and rarely lipodystrophy), and cosegregates with cardiovascular disease in multiple families (PMID: 11897440, 25469153, 30287275, 31983221, 34773379). It is suggested to be an Italian founder variant. Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.873). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PM2_Supporting, PP3.
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:2
PS4, PP1_strong, PM2, PP2, PP3
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.
not specified Pathogenic:1
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.
LMNA-related disorder Pathogenic:1
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.
Laminopathy Pathogenic:1
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD (v4) <0.01 (14 heterozygotes, 0 homozygotes); 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); Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from glutamic acid to lysine; This variant is heterozygous; This gene is associated with both recessive and dominant disease (OMIM); An alternative amino acid change at the same position has been observed in gnomAD (v2) (p.(Glu317Asp): 1 heterozygote, 0 homozygotes); Variant is located in the annotated coiled coil filament (DECIPHER); 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); The condition associated with this gene has incomplete penetrance. Pathogenic variants have been reported with reduced penetrance in families with Emery-Dreifuss muscular dystrophy and LMNA-related disorders (PMID: 20301609). Age-related penetrance has been reported for LMNA-related dilated cardiomyopathy (PMID: 20301717); Variants in this gene are known to have variable expressivity (OMIM); Inheritance information for this variant is not currently available in this individual.
Cardiomyopathy Pathogenic:1
Charcot-Marie-Tooth disease type 2 Pathogenic:1
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; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48093). 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%. For these reasons, this variant has been classified as Pathogenic.
Primary familial dilated cardiomyopathy Pathogenic:1
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.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at