NM_170707.4:c.1750C>A
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_170707.4(LMNA):c.1750C>A(p.Arg584Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R584H) 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 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1750C>A | p.Arg584Ser | missense_variant | Exon 11 of 12 | ENST00000368300.9 | NP_733821.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2 Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 584 of the LMNA protein (p.Arg584Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. 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%. This variant disrupts the p.Arg584 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10999845, 11078466, 24623722). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 10939567) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at