Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000182355 | SCV000234668 | pathogenic | not provided | 2016-04-24 | criteria provided, single submitter | clinical testing | c.356+1 G>A: IVS1+1 G>A in intron 1 of the LMNA gene (NM_170707.2). Mutations in the LMNA gene have been reported in up to 10% of patients with autosomal dominant familial dilated cardiomyopathy with conduction defects (Muschke P et al., 2007) and have been associated with several disorders of striated muscle, nerve, adipose, and vascular tissue, collectively referred to as the laminopathies (Hershberger R et al., 2009). Although the c.356+1 G>A mutation has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice donor site in intron 1 and is predicted to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site mutations at this location (c.356+1 G>C and c.356+1 G>T) have been reported in association with cardiomyopathy and/or laminopathy. In summary, c.356+1 G>A in the LMNA gene is interpreted as a disease-causing mutation. The variant is found in DCM-CRDM, CARDIOMYOPATHY panel(s). |
| Invitae | RCV000689313 | SCV000816956 | pathogenic | Charcot-Marie-Tooth disease type 2 | 2020-10-19 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individuals with clinical features of LMNA-related conditions (PMID: 23062543, Invitae). ClinVar contains an entry for this variant (Variation ID: 200933). For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LMNA are known to be pathogenic (PMID: 18585512, 18926329). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 1 of the LMNA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |