Submissions for variant NM_170707.4(LMNA):c.1142_1157+1del

dbSNP: rs1553265755

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000599189	SCV000700984	pathogenic	not provided	2016-01-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000599189	SCV000710008	pathogenic	not provided	2020-11-11	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID#496992; Landrum et al., 2016); Frameshift variant which eliminates five amino acids at the end of exon 6 and destroys the canonical splice donor site at the +1 position of intron 6 and is predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30564623)
Invitae	RCV001231259	SCV001403773	pathogenic	Charcot-Marie-Tooth disease type 2	2020-03-18	criteria provided, single submitter	clinical testing	This variant disrupts the p.Glu383 and p.Arg386 amino acid residues in LMNA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26098624, 23427149, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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 has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 496992). This variant is not present in population databases (ExAC no frequency). This variant results in the deletion of part of exon 6 (c.1142_1157+1del) of the LMNA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics	RCV002456296	SCV002616216	likely pathogenic	Cardiovascular phenotype	2020-07-17	criteria provided, single submitter	clinical testing	The c.1142_1157+1del17 variant results from a deletion of 17 nucleotides between positions c.1142 and c.1157+1 and involves the canonical splice donor site after coding exon 6 of the LMNA gene. The canonical splice donor site is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.