Submissions for variant NM_170707.4(LMNA):c.1609-3C>G

dbSNP: rs267607581

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154514	SCV000204185	likely pathogenic	Primary dilated cardiomyopathy	2020-07-23	criteria provided, single submitter	clinical testing	The c.1609-3C>G variant in LMNA has been identified in one individual with limb girdle muscular dystrophy and was found to segregate with disease in at least 3 affected relatives (Chrestian 2008 PMID: 18714801), all of whom had cardiac involvement. It was also identified by our laboratory in one individual with DCM (LMM data) and has reported in ClinVar by other clinical laboratories (Variation ID 66856). This variant was absent from large population studies. Two studies using patient RNA and a cell-based splicing assay have independently shown that this variant results in the skipping of exon 10, leading to an in-frame deletion of 30 amino acids (Chrestian 2008 PMID: 18714801, Ito 2017 PMID: 28679633). In summary, although additional studies are required to fully establish its clinical significance, the c.1609-3C>G variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3_Moderate, PS4_Supporting, PP1.
Genetic Services Laboratory, University of Chicago	RCV000503283	SCV000595635	pathogenic	Dilated cardiomyopathy 1A	2013-02-08	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623500	SCV000740350	pathogenic	Primary familial hypertrophic cardiomyopathy	2017-01-25	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001174242	SCV001337371	likely pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Invitae	RCV001854174	SCV002237777	pathogenic	Charcot-Marie-Tooth disease type 2	2023-01-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10, but is expected to preserve the integrity of the reading-frame (PMID: 18714801). ClinVar contains an entry for this variant (Variation ID: 66856). This variant is also known as IVS9-3C>G. This variant has been observed in individual(s) with clinical features of autosomal dominant LMNA-related conditions (PMID: 18714801, 24503780). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 9 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.
Ambry Genetics	RCV002390206	SCV002703104	likely pathogenic	Cardiovascular phenotype	2023-02-09	criteria provided, single submitter	clinical testing	The c.1609-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 10 in the LMNA gene. This variant was detected in a proband reported to have limb girdle muscular dystrophy and cardiac conduction disease and segregated with disease in several relatives with primarily cardiac findings including cardiac conduction disease, dysrhythmia, dilated cardiomyopathy or sudden death with or without muscle weakness. RNA studies on a sample from the proband indicated abnormal splicing leading to skipping of exon 10 (Chrestian N et al. Can J Neurol Sci, 2008 Jul;35:331-4). This variant was also detected in an individual from a dilated cardiomyopathy cohort (Pugh TJ et al. Genet. Med. 2014 Aug;16(8):601-8). This alteration was also detected in a Charcot-Marie-Tooth cohort; however, clinical details were limited (Volodarsky M et al. J Med Genet, 2021 Apr;58:284-288). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000057338	SCV003915401	likely pathogenic	not provided	2022-10-06	criteria provided, single submitter	clinical testing	Identified in a family with LGMD in several symptomatic individuals but also in several asymptomatic adults (Chrestian et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing, and published RNA studies and mini-gene assay support a significant splicing defect (Chrestian et al., 2008; Ito et al., 2017); This variant is associated with the following publications: (PMID: 25525159, 24503780, 18714801, 24846508, 32376792, 24459210, 10939567, 36138163, 28679633)
PreventionGenetics, part of Exact Sciences	RCV004537257	SCV004746506	likely pathogenic	LMNA-related disorder	2024-02-20	criteria provided, single submitter	clinical testing	The LMNA c.1609-3C>G variant is predicted to interfere with splicing. This variant has been reported in a large French Canadian family in which some individuals had a limb girdle type muscle weakness as well as cardiac conduction phenotype (Chrestian. et al. 2008. PubMed ID: 18714801). However, this variant was also found in at least 3 individuals in this family with a clinical evaluation of no muscle weakness or cardiac symptoms (age of clinical workup was 30-40). RNA studies did indicate that this variant resulted in exon skipping of exon 10 and an in-frame deletion of 30 amino acids and a mini-gene assay also indicates this variant results in aberrant splicing (Ito et al. 2017. PubMed ID: 28679633). This variant was also reported in a single patient with a clinical diagnosis and family history of dilated cardiomyopathy (Pugh et al. 2014. PubMed ID: 24503780). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic.
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057338	SCV000088451	not provided	not provided		no assertion provided	not provided