Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ce |
RCV000487579 | SCV000574793 | uncertain significance | not provided | 2023-04-01 | criteria provided, single submitter | clinical testing | LMNA: PM2, PP3 |
Color Diagnostics, |
RCV001184326 | SCV001350278 | uncertain significance | Cardiomyopathy | 2023-04-20 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with serine at codon 110 of the LMNA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three unrelated individuals affected with dilated cardiomyopathy, and in three asymptomatic family members of one of these individuals (PMID: 23328570, 32880476; Botto et al., 2011). This variant has been identified in 1/242144 chromosomes 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. |
Invitae | RCV002525984 | SCV003523517 | uncertain significance | Charcot-Marie-Tooth disease type 2 | 2023-12-07 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 110 of the LMNA protein (p.Arg110Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 23328570, 32880476). ClinVar contains an entry for this variant (Variation ID: 424916). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect LMNA function (PMID: 34862408). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. |