Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193316 | SCV001362067 | uncertain significance | not specified | 2019-04-08 | criteria provided, single submitter | clinical testing | Variant summary: LMNA c.1237G>T (p.Gly413Cys) results in a non-conservative amino acid change located in the Nesprin 2 binding site domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 245102 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1237G>T in individuals affected with Cardiomyopathy has been reported. Co-occurrences with other pathogenic variant(s) have been reported at our laboratory (SCN5A c.535C>T, p.R179*), providing supporting evidence for a benign role. One publication reports experimental evidence evaluating an impact on protein function demonstrating no impact on the distribution of interaction partners in the Nuclear Envelope components examined, namely Lamin B1 or Emerin (Yang_2013). However, this does not allow convincing conclusions about the variant effect. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Labcorp Genetics |
RCV001859170 | SCV002266505 | uncertain significance | Charcot-Marie-Tooth disease type 2 | 2023-06-05 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this missense change does not substantially affect LMNA function (PMID: 23977161). 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: 928831). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is present in population databases (rs766811975, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 413 of the LMNA protein (p.Gly413Cys). |
| Fulgent Genetics, |
RCV002491587 | SCV002781493 | uncertain significance | Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome; Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; Heart-hand syndrome, Slovenian type; Hutchinson-Gilford syndrome; Familial partial lipodystrophy, Dunnigan type; Mandibuloacral dysplasia with type A lipodystrophy; Congenital muscular dystrophy due to LMNA mutation; Emery-Dreifuss muscular dystrophy 3, autosomal recessive; Restrictive dermopathy 2 | 2021-09-11 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV003490106 | SCV004236247 | uncertain significance | not provided | 2023-03-15 | criteria provided, single submitter | clinical testing |