rs267607591
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_170707.4(LMNA):c.898G>A(p.Asp300Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D300G) has been classified as Pathogenic.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.898G>A | p.Asp300Asn | missense_variant | 5/12 | ENST00000368300.9 | |
LMNA | NM_005572.4 | c.898G>A | p.Asp300Asn | missense_variant | 5/10 | ENST00000677389.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.898G>A | p.Asp300Asn | missense_variant | 5/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.898G>A | p.Asp300Asn | missense_variant | 5/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 08, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 300 of the LMNA protein (p.Asp300Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant LMNA-related conditions (PMID: 19095983, 25327215, 29047356, 32548202). ClinVar contains an entry for this variant (Variation ID: 66952). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects LMNA function (PMID: 30696354). This variant disrupts the p.Asp300 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been observed in individuals with LMNA-related conditions (PMID: 23666920, 30123186, 32954377), which suggests that this may be a clinically significant amino acid residue. 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. - |
Lipodystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 24, 2014 | - - |
Dilated cardiomyopathy 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Apr 08, 2022 | The c.898G>A variant in LMNA has previously been reported in a heterozygous state in over ten individuals with variable features of laminopathies such as lipodystrophy, progeria, diabetes, non-alcoholic fatty liver disease, and early onset coronary artery disease and cardiomyopathy [PMID:19095983, 28938416,29047356, 32413188, 32548202, 32901917, 33502018], and it has been deposited in ClinVar [ClinVar ID: 66952] as Variant of Uncertain Significance for Charcot-Marie-Tooth disease, type 2 and Likely Pathogenic for Lipodystrophy. The c.898G>A variant is absent from population databases (gnomAD v2.1.1 and v3.1.2,TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.898G>A variant is located inexon 5 of this 12-exon gene, and predicted to replace an evolutionarily conserved aspartate amino acid with asparagine at position 300 within the intermediate filament domain of the encoded protein [UniProtKB ID: P02545]. In silico predictions are moderately in favor of damaging effect for p.(Asp300Asn) [CADD v1.6 = 29.9,REVEL = 0.606]. Cardiac myocytes of mice models carrying p.Asp300Asn allele were shown to result in myocardial fibrosis, apoptosis, and cardiac dysfunction [PMID:30696354]. Variants affecting the same residue (p.(Asp300Gly) and p.(Asp300His)) have also been reported in literature in individuals with laminopathies [PMID:22991222, 23666920, 25327215, 30123186, 32954377]. Based on available evidence this c.898G>A p.(Asp300Asn) variant identified in LMNA in is classified as Pathogenic. - |
not provided Other:1
not provided, no classification provided | literature only | Epithelial Biology; Institute of Medical Biology, Singapore | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at