ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.1608+2T>G

dbSNP: rs2102896324
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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 RCV001388734 SCV001589810 pathogenic Charcot-Marie-Tooth disease type 2 2020-10-08 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. 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). 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. Disruption of this splice site has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 24915601, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 9 of the LMNA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics RCV002395876 SCV002703685 likely pathogenic Cardiovascular phenotype 2020-12-02 criteria provided, single submitter clinical testing The c.1608+2T>G intronic variant results from a T to G substitution two nucleotides after coding exon 9 in the LMNA gene. This variant was not reported in population-based 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 donor site and will result in the creation or strengthening of a novel 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. As such, this alteration is classified as likely pathogenic.

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