Submissions for variant NM_170707.4(LMNA):c.1380+1G>A

dbSNP: rs267607552

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000057283	SCV000234699	pathogenic	not provided	2014-05-28	criteria provided, single submitter	clinical testing	c.1380+1 G>A: IVS7+1 G>A in intron 7 of the LMNA gene (NM_170707.2). The c.1380+1 G>A mutation in the LMNA gene has been reported previously in at least 2 patients with DCM, and was not reported in at least 480 healthy control chromosomes (van Tintelen J et al., 2007; Magagnotti C et al., 2012). This mutation destroys the canonical splice donor site in intron 7 and is predicted to cause abnormal gene splicing. Other splice site mutations in the LMNA gene have been reported in association with LMNA-related disorders. In summary, c.1380+1 G>A in the LMNA gene is interpreted as a disease-causing mutation. The variant is found in DCM-CRDM panel(s).
Invitae	RCV000697969	SCV000826605	pathogenic	Charcot-Marie-Tooth disease type 2	2023-04-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 66817). This variant is also known as IVS7+1G>A. Disruption of this splice site has been observed in individuals with laminopathies (PMID: 18035086, 22326558). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 7 of the LMNA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
Ambry Genetics	RCV002381366	SCV002700971	pathogenic	Cardiovascular phenotype	2022-01-27	criteria provided, single submitter	clinical testing	The c.1380+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the LMNA gene. This variant has been detected in multiple individual with dilated cardiomyopathy (DCM) and/or cardiac conduction defects, and co-segregation with disease has been reported in some families (van Tintelen JP et al. Am Heart J, 2007 Dec;154:1130-9; Millat G et al. Eur J Med Genet, 2011 Aug;54:e570-5; Jansweijer JA et al. Eur J Heart Fail, 2017 04;19:512-521; Park J et al. Genet Med, 2020 01;22:102-111). This variant has also been reported in an individual with DCM and limb-girdle muscular dystrophy (LGMD) (Magagnotti C et al. Biochim Biophys Acta, 2012 Jun;1822:970-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057283	SCV000088396	not provided	not provided		no assertion provided	not provided
GenomeConnect - Invitae Patient Insights Network	RCV001535753	SCV001749888	not provided	Dilated cardiomyopathy 1A; Charcot-Marie-Tooth disease type 2B1; Emery-Dreifuss muscular dystrophy 2, autosomal dominant; 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		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 09-29-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.