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

dbSNP: rs773132143

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194428	SCV001363976	uncertain significance	not specified	2019-08-12	criteria provided, single submitter	clinical testing	Variant summary: IKBKAP c.3572+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: five 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 4.8e-05 in 251420 control chromosomes (gnomAD). This frequency is not higher than expected maximum for a pathogenic variant in IKBKAP causing Familial Dysautonomia (4.8e-05 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3572+5G>A in individuals affected with Familial Dysautonomia and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001220783	SCV001392794	uncertain significance	not provided	2019-11-13	criteria provided, single submitter	clinical testing	This sequence change falls in intron 33 of the ELP1 gene. It does not directly change the encoded amino acid sequence of the ELP1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs773132143, ExAC 0.02%). This variant has not been reported in the literature in individuals with ELP1-related conditions. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV001194428	SCV002755757	uncertain significance	not specified	2021-12-30	criteria provided, single submitter	clinical testing	The c.3572+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 32 in the IKBKAP gene. 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002504221	SCV002815798	uncertain significance	Medulloblastoma; Familial dysautonomia	2022-03-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001833753	SCV002082013	uncertain significance	Familial dysautonomia	2020-05-06	no assertion criteria provided	clinical testing