Submissions for variant NM_170707.4(LMNA):c.1381-5G>A

gnomAD frequency: 0.00008  dbSNP: rs730880133

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484067	SCV000574093	uncertain significance	not provided	2022-11-08	criteria provided, single submitter	clinical testing	Reported in an individual with DCM (Ferradini et al., 2021); Using a mini-gene assay, this variant resulted in aberrant splicing (Ito et al., 2017); however, it is unclear whether this assay replicates in vivo conditions and further description of the aberrant splice product observed was not provided; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30402260, 34768595, 28679633)
Fulgent Genetics, Fulgent Genetics	RCV002478468	SCV000896162	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	2022-05-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815746	SCV000956215	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs730880133, gnomAD 0.03%). This variant has been observed in individual(s) with clinical features of autosomal dominant LMNA-related conditions (PMID: 28679633, 34768595). ClinVar contains an entry for this variant (Variation ID: 180405). Studies have shown that this variant results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 28679633). 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, LLC DBA Color Health	RCV001185511	SCV001351743	uncertain significance	Cardiomyopathy	2023-03-22	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the -5 position of intron 7 of the LMNA gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing by weakening the native splice acceptor and creating a new in-frame acceptor, resulting in the in-frame insertion of one amino acid. A functional mini-gene assay has shown that this variant significantly alters splicing in comparison with the reference sequence (PMID: 28679633). This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 34788595) and in an individual affected with hypertrophic cardiomyopathy (PMID: 28679633). This variant has been identified in 16/280420 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.
Ambry Genetics	RCV002381508	SCV002699829	uncertain significance	Cardiovascular phenotype	2024-02-06	criteria provided, single submitter	clinical testing	The c.1381-5G>A intronic variant results from a G to A substitution 5 nucleotides upstream from coding exon 8 in the LMNA gene. This variant was identified in an individual with hypertrophic cardiomyopathy; a minigene assay in HEK293 cells demonstrated an increase in aberrant splicing compared to wild type (Ito K et al. Proc. Natl. Acad. Sci. U.S.A., 2017 07;114:7689-7694). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on available evidence to date, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000484067	SCV003814695	uncertain significance	not provided	2020-08-14	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000157297	SCV000207029	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-07-21	no assertion criteria provided	clinical testing
Sangiuolo Lab - Medical Genetics Laboratory, Tor Vergata University	RCV001775087	SCV001593112	uncertain significance	Dilated cardiomyopathy 1A	2021-04-27	no assertion criteria provided	clinical testing