rs28928902
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_170707.4(LMNA):āc.1411C>Gā(p.Arg471Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,144 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R471P) has been classified as Uncertain significance.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.1411C>G | p.Arg471Gly | missense_variant | 8/12 | ENST00000368300.9 | |
LMNA | NM_005572.4 | c.1411C>G | p.Arg471Gly | missense_variant | 8/10 | ENST00000677389.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.1411C>G | p.Arg471Gly | missense_variant | 8/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.1411C>G | p.Arg471Gly | missense_variant | 8/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74328
ClinVar
Submissions by phenotype
not provided Uncertain:1Other:1
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 18, 2022 | PP3, PM2_supporting - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 08, 2022 | 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. 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. This variant disrupts the p.Arg471 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18646565, 23582089, 27532257, 29943882). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 66824). This missense change has been observed in individual(s) with clinical features of autosomal dominant lipodystrophy (PMID: 18041775). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 471 of the LMNA protein (p.Arg471Gly). - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2022 | The p.R471G variant (also known as c.1411C>G), located in coding exon 8 of the LMNA gene, results from a C to G substitution at nucleotide position 1411. The arginine at codon 471 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in an individual with dilated cardiomyopathy (DCM) and cardiac conduction disease, as well as in two siblings with familial partial lipodystrophy (Muschke P et al. Am. J. Med. Genet. A, 2007 Dec;143A:2810-4; Ambry internal data). Another alteration at the same codon, p.R471H (c.1412G>A), has been reported in association with laminopathy and DCM (Astejada MN et al. Acta Myol. 2007; 26(3):159-64). 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 majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at