ClinVar Miner

Submissions for variant NM_003640.5(ELP1):c.3572+1G>A

gnomAD frequency: 0.00001  dbSNP: rs571348995
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001377355 SCV001574672 likely pathogenic not provided 2021-12-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 33 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). This variant is present in population databases (rs571348995, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ELP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 651159). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000806459 SCV002570744 likely pathogenic Familial dysautonomia 2022-07-08 criteria provided, single submitter clinical testing Variant summary: IKBKAP (also known as ELP1) c.3572+1G>A 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: Three predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251438 control chromosomes (gnomAD). c.3572+1G>A has been reported in the literature in one individual affected with medulloblastoma (Waszak_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Natera, Inc. RCV000806459 SCV002082014 likely pathogenic Familial dysautonomia 2021-07-13 no assertion criteria provided clinical testing

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