rs28933092
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_170707.4(LMNA):c.608A>G(p.Glu203Gly) 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. 14/22 in silico tools predict a damaging 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. E203K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_170707.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LMNA | NM_170707.4 | c.608A>G | p.Glu203Gly | missense_variant | 3/12 | ENST00000368300.9 | |
LMNA | NM_005572.4 | c.608A>G | p.Glu203Gly | missense_variant | 3/10 | ENST00000677389.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LMNA | ENST00000368300.9 | c.608A>G | p.Glu203Gly | missense_variant | 3/12 | 1 | NM_170707.4 | P1 | |
LMNA | ENST00000677389.1 | c.608A>G | p.Glu203Gly | missense_variant | 3/10 | NM_005572.4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 33
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 | Jun 17, 2023 | 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.Glu203 amino acid residue in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11561226, 18606848, 18795223, 20160190, 22464770). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LMNA function (PMID: 11792809, 16772334, 18606848, 25319090, 34862408). 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. ClinVar contains an entry for this variant (Variation ID: 14484). This missense change has been observed in individual(s) with clinical features of autosomal dominant LMNA-related conditions (PMID: 10580070). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 203 of the LMNA protein (p.Glu203Gly). - |
Primary dilated cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 21, 2015 | The p.Glu203Gly variant in LMNA has been reported in 1 family with DCM and condu ction system disease (Fatkin 1999), where it segregated with disease in 5 indivi duals with DCM and 4 individuals with AV block (Fatkin 1999, C. Seidman, pers co mm). One functional study suggests that this variant impacts the protein (Zhang 2008), while another had inconclusive findings (Ostlund 2001); however, these in vitro assays may not accurately represent biological function. This variant has not been identified in large population studies, but it is listed in dbSNP (rs2 8933092) without frequency information. Finally, another pathogenic variant has also been reported at this position (Glu203Lys; Jakobs 2001). In summary, this v ariant meets our criteria to be classified as pathogenic (http://pcpgm.partners. org/LMM) based upon segregation studies and absence from controls. - |
Dilated cardiomyopathy 1A Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 02, 1999 | - - |
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