Submissions for variant NM_003640.5(ELP1):c.2803A>T (p.Thr935Ser)

gnomAD frequency: 0.00006  dbSNP: rs145484092

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000351107	SCV000476558	uncertain significance	Familial dysautonomia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000757403	SCV000816487	uncertain significance	not provided	2022-08-10	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 935 of the ELP1 protein (p.Thr935Ser). This variant is present in population databases (rs145484092, gnomAD 0.008%). 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: 364564). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757403	SCV000885609	uncertain significance	not provided	2017-06-15	criteria provided, single submitter	clinical testing	The p.Thr935Ser variant (rs14548409) has been reported as a variant of uncertain significance that was detected twice in a large cohort of patients with idiopathic peripheral neuropathy (Antoniardi 2015). This variant is also listed in the ClinVar database as a variant of uncertain significance (Variation ID: 364564). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in European populations of 0.008% (identified on 10 out of 126,420 chromosomes). The threonine at codon 935 is moderately conserved (Alamut software v2.9.0), however several species including cape golden mole, lizard, Atlantic cod and lamprey have a serine at this position, suggesting this change may be evolutionary tolerated. Computational analyses return mixed predictions regarding the effect on IKBKAP protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: disease causing).
GeneDx	RCV000757403	SCV001994756	uncertain significance	not provided	2019-03-21	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291624	SCV002584771	uncertain significance	Medulloblastoma	2022-12-19	criteria provided, single submitter	clinical testing	The ELP1 c.2803A>T (p.Thr935Ser) missense change has a maximum subpopulation frequency of 0.0078% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with Charcot-Marie-Tooth disease and in an individual with hereditary motor neuropathy (PMID: 26392352). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Ambry Genetics	RCV004022094	SCV002755068	uncertain significance	not specified	2022-01-22	criteria provided, single submitter	clinical testing	The c.2803A>T (p.T935S) alteration is located in exon 26 (coding exon 25) of the IKBKAP gene. This alteration results from a A to T substitution at nucleotide position 2803, causing the threonine (T) at amino acid position 935 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV000351107	SCV001457896	uncertain significance	Familial dysautonomia	2020-09-16	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000757403	SCV001917276	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000757403	SCV001927242	uncertain significance	not provided		no assertion criteria provided	clinical testing