ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.937-1G>A

dbSNP: rs1553265606
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000653870 SCV000775760 likely pathogenic Charcot-Marie-Tooth disease type 2 2019-06-24 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the LMNA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with LMNA-related disease. 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. Donor and acceptor splice site variants 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV002369757 SCV002684937 likely pathogenic Cardiovascular phenotype 2021-05-11 criteria provided, single submitter clinical testing The c.937-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 6 of the LMNA gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor 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. As such, this alteration is classified as likely pathogenic.

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