ClinVar Miner

Submissions for variant NM_003640.5(ELP1):c.1461-2A>G

gnomAD frequency: 0.00001  dbSNP: rs866046915
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000596965 SCV000703836 uncertain significance not provided 2018-01-18 criteria provided, single submitter clinical testing
Counsyl RCV000668028 SCV000792571 likely pathogenic Familial dysautonomia 2017-07-10 criteria provided, single submitter clinical testing
Invitae RCV000596965 SCV001380805 likely pathogenic not provided 2022-12-20 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 498695). This variant has not been reported in the literature in individuals affected with ELP1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 13 of the ELP1 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 ELP1 are known to be pathogenic (PMID: 18303054, 24173031).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000668028 SCV002051440 likely pathogenic Familial dysautonomia 2021-11-16 criteria provided, single submitter clinical testing Variant summary: IKBKAP (also known as ELP1) c.1461-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: one predict the variant abolishes a 3 prime acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251032 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1461-2A>G in individuals affected with Familial Dysautonomia and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as variant of uncertain significance (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc. RCV000668028 SCV002082130 likely pathogenic Familial dysautonomia 2020-12-29 no assertion criteria provided clinical testing

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