Submissions for variant NM_170707.4(LMNA):c.937-7C>G

gnomAD frequency: 0.00006  dbSNP: rs267607681

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000057488	SCV000513494	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Reported in a dataset of LMNA variants identified in individuals with cardiomyopathy as reported in ClinVar and/or by a clinical laboratory, or observed as rare variants in the Exome Aggregation Consortium (Ito et al., 2017); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 32376792, 18796515, 28679633)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530832	SCV000657827	uncertain significance	Charcot-Marie-Tooth disease type 2	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change falls in intron 5 of the LMNA gene. It does not directly change the encoded amino acid sequence of the LMNA protein. This variant is present in population databases (rs267607681, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of LMNA-related conditions (PMID: 22464770, 28679633, 32376792). ClinVar contains an entry for this variant (Variation ID: 66959). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV000772012	SCV000904968	uncertain significance	Cardiomyopathy	2023-04-20	criteria provided, single submitter	clinical testing	This variant causes a C to G nucleotide substitution at the -7 position of intron 5 of the LMNA gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. An in vitro mini-gene assay has shown that this variant may cause skipping of exon 6 (PMID: 28679633). This variant has been reported in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has been identified in 10/277870 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.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV001172638	SCV001335701	likely benign	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000440584	SCV002766546	uncertain significance	not specified	2022-11-14	criteria provided, single submitter	clinical testing	Variant summary: LMNA c.937-7C>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 3' acceptor site, whereas one predicts the variant has no significant impact on splicing. At least one publication reports experimental evidence that this variant affects mRNA splicing, impacting approximately 55% of all transcripts, with 45% exhibiting normal splicing (e.g. Ito_2017). The variant allele was found at a frequency of 3.6e-05 in 277870 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in LMNA causing Dilated Cardiomyopathy (3.6e-05 vs 0.0001), allowing no conclusion about variant significance. c.937-7C>G has been reported in the literature in a setting of multi-gene panel testing as a VUS in one individual affected with Dilated Cardiomyopathy (e.g. Lakdawala_2012). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Two classified the variant as VUS and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003996513	SCV004824689	uncertain significance	Primary dilated cardiomyopathy	2023-12-01	criteria provided, single submitter	clinical testing	This variant causes a C to G nucleotide substitution at the -7 position of intron 5 of the LMNA gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. An in vitro mini-gene assay has shown that this variant may cause skipping of exon 6 (PMID: 28679633). This variant has been reported in an individual suspected to be affected with Charcot-Marie-Tooth disease (PMID: 32376792). This variant has been identified in 10/277870 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003996513	SCV004848920	uncertain significance	Primary dilated cardiomyopathy	2019-04-04	criteria provided, single submitter	clinical testing	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This is an intronic variant. It is not predicted to affect splicing but an in vitro study shows that the variant has an effect on splicing (Ito 2017). Clinvar: LB (GeneDx), VUS (Invitae). Gnomad: 0.012% (4 alleles).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786335	SCV005399353	uncertain significance	Dilated cardiomyopathy 1A	2024-10-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3A-VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Missense variants have been reported to result in gain-of-function, as well as dominant-negative, and are associated to a more severe and earlier phenotype. Truncating variants have been shown to result in loss-of-function associated with a milder and later-onset disease (PMID: 17377071). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance. Emery-Dreifuss muscular dystrophy has been reported to have incomplete penetrance (PMID: 20301609). (N) 0212 - Non-canonical splice variant without proven consequence on splicing (intron 5). RNA studies previously performed at VCGS with this proband’s mother sample were inconclusive. (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a dominant or recessive condition (10 heterozygotes, 0 homozygotes). (P) 0309 - Multiple alternative nucleotide changes at the same position have been observed in gnomAD (highest allele count: 1 heterozygote, 0 homozygotes). (N) 0506 - Abnormal splicing is not predicted and nucleotide is poorly conserved. However, this variant might enhance abnormal use of an available cryptic 3’ splice site (personal communication). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported as part of a haplotype in a patient with severe mandibuloacral dysplasia and it has also been found in patients with dilated cardiomyopathy (ClinVar; LOVD; PMID: 18796515; PMID: 28679633). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant alone. However, functional studies showing impact in protein function were performed using fibroblasts from a patient with a haplotype containing this variant along with others (PMID: 18796515). Therefore, it is not possible to determine which of the variants within the haplotype is functional. (N) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Epithelial Biology; Institute of Medical Biology, Singapore	RCV000057488	SCV000088602	not provided	not provided		no assertion provided	not provided
Clinical Genetics, Academic Medical Center	RCV000440584	SCV002034605	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000057488	SCV002036808	likely benign	not provided		no assertion criteria provided	clinical testing