chr1-156135260-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1
The NM_170707.4(LMNA):c.884C>T(p.Ser295Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,512 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. S295P) 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: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.884C>T | p.Ser295Leu | missense_variant | Exon 5 of 12 | ENST00000368300.9 | NP_733821.1 | |
LMNA | NM_005572.4 | c.884C>T | p.Ser295Leu | missense_variant | Exon 5 of 10 | ENST00000677389.1 | NP_005563.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.884C>T | p.Ser295Leu | missense_variant | Exon 5 of 12 | 1 | NM_170707.4 | ENSP00000357283.4 | ||
LMNA | ENST00000677389.1 | c.884C>T | p.Ser295Leu | missense_variant | Exon 5 of 10 | NM_005572.4 | ENSP00000503633.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152256Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000239 AC: 6AN: 250592 AF XY: 0.0000369 show subpopulations
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461256Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12AN XY: 726934 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74384 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:5
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Reported previously as a variant of uncertain significance in a parent whose child had a diagnosis of heterotaxy; however, no further clinical information was provided on the parent and it was unclear if the child also harbored the variant (Chetruengchai and Shotelersuk, 2022); Reported previously in an individual diagnosed with HCM; however, further clinical, family history, and segregation details were unavailable (Lopes et al., 2015); Reported previously as a variant of uncertain significance in a patient with non-ischemic cardiomyopathy and previous heart transplantation; however, further clinical and segregation information was provided (Boen et al., 2022); 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: 28663758, 10939567, 34621001, 35581137, 25351510) -
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Primary dilated cardiomyopathy Uncertain:2
This missense variant replaces serine with leucine at codon 295 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30847666), in an individual affected with unspecified cardiomyopathy (PMID: 35581137), and in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 7/281984 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. -
This sequence change results in a missense variant in the LMNA gene (p.(Ser295Leu)) (PP2; based on GnomAd constraint matrix). The variant is described in LVOD as variant of unknown significance (LMNA_000421). This variant is present in GnomAD with a prevalence of 7/276586.This variant has been described in literature in an individual with HCM (PMID: 25351510) but was also seen in a control-population (PMID: 28663758) .The variant affects a weakly conserved nucleotide and a moderately conserved amino acid. Prediction programs classify the variant as benign (Align GVGD: C0; Polyphen-2-HumDiv: benign ; Polyphen-2-HumVar: benign; SIFT: tolerated; MutationTaster: no result) (BP4). It is located in the intermediate filament rod domain of the LMNA protein. Functional assays have not been performed for this variant. We identified this variant in a 2 unrelated patients with DCM and a third unrelated patient presenting with refractory Ventricular tachycardia in absence of structural cardiac abnormalities. No data on segregation were available. In conclusion this variant was classified as variant of unknown significance according to ACMG-guidelines (insufficient data, criteria for other classification are not met: BS4, PP2). -
Cardiomyopathy Uncertain:1
This missense variant replaces serine with leucine at codon 295 of the LMNA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 30847666), in an individual affected with unspecified cardiomyopathy (PMID: 35581137), and in an individual affected with hypertrophic cardiomyopathy (PMID: 25351510). This variant has been identified in 7/281984 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
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 295 of the LMNA protein (p.Ser295Leu). This variant is present in population databases (rs769210828, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 20848652, 30847666, 34621001; internal data). ClinVar contains an entry for this variant (Variation ID: 518983). 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%. Experimental studies have shown that this missense change does not substantially affect LMNA function (PMID: 34862408). 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. -
Cardiovascular phenotype Uncertain:1
The p.S295L variant (also known as c.884C>T), located in coding exon 5 of the LMNA gene, results from a C to T substitution at nucleotide position 884. The serine at codon 295 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort and dilated cardiomyopathy cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Boen HM et al. J Heart Lung Transplant, 2022 Sep;41:1218-1227). This variant was detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This alteration has also been reported as a secondary finding in an exome cohort (Chetruengchai W et al. J Hum Genet, 2022 Mar;67:137-142). Another alteration affecting this amino acid (p.S295P, c.883T>C) has been reported in a single individual with muscular dystrophy and cardiomyopathy with conduction disease (Scharner J et al. Hum. Mutat., 2011 Feb;32:152-67). This amino acid position is not well conserved in available 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at