Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000622044 | SCV000736318 | uncertain significance | Cardiovascular phenotype | 2022-02-22 | criteria provided, single submitter | clinical testing | The c.1873_1874delAGinsCC variant (also known as p.S625P), located in coding exon 11 of the LMNA gene, results from an in-frame deletion of AG and insertion of CC at nucleotide positions 1873 to 1874. This results in the substitution of the serine residue for a proline residue at codon 625, an amino acid with similar properties. This variant co-occurred with a variant in another cardiac related gene in a proband with hypertrophic cardiomyopathy from a sudden death cohort (Quenin P. Circ Arrhythm Electrophysiol. 2017 Sep;10(9)). Another variant affecting this codon (p.S625R) has been detected in a dilated cardiomyopathy cohort; however, details were limited (Horvat C et al. Genet Med, 2019 01;21:133-143). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000822504 | SCV000963311 | uncertain significance | Charcot-Marie-Tooth disease type 2 | 2022-08-23 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 625 of the LMNA protein (p.Ser625Pro). This variant is present in population databases (no rsID available, gnomAD 0.4%). This variant has not been reported in the literature in individuals affected with LMNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 518817). 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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. |
| Color Diagnostics, |
RCV001185275 | SCV001351450 | uncertain significance | Cardiomyopathy | 2023-01-09 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with proline at codon 625 of the LMNA protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with sudden cardiac death (PMID: 28912206). A different DNA substitution with the same protein effect c.1875C>A (p.Ser625Pro) has been reported in an individual affected with dilated cardiomyopathy (PMID: 29892087). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Fulgent Genetics, |
RCV002498997 | SCV002777156 | 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 | 2022-01-04 | criteria provided, single submitter | clinical testing |