ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.639+1G>T

dbSNP: rs869125101
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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 RCV001065501 SCV001230460 likely pathogenic Charcot-Marie-Tooth disease type 2 2023-06-15 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with LMNA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 3 of the LMNA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). ClinVar contains an entry for this variant (Variation ID: 859400). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
Ambry Genetics RCV002355077 SCV002655298 likely pathogenic Cardiovascular phenotype 2021-07-23 criteria provided, single submitter clinical testing The c.639+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 3 of the LMNA gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing. 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. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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