Submissions for variant NM_003640.5(ELP1):c.947C>T (p.Pro316Leu)

gnomAD frequency: 0.00026  dbSNP: rs374814563

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000302687	SCV000476583	uncertain significance	Familial dysautonomia	2018-01-12	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.
GeneDx	RCV000493897	SCV000583006	uncertain significance	not provided	2017-05-18	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the IKBKAP gene. The P316L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P316L variant is observed in 12/10,406 (0.1%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P316L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000493897	SCV000829353	uncertain significance	not provided	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 316 of the ELP1 protein (p.Pro316Leu). This variant is present in population databases (rs374814563, gnomAD 0.08%). 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: 364577). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV002461128	SCV002755431	likely benign	Inborn genetic diseases	2021-08-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002488820	SCV002799732	uncertain significance	Medulloblastoma; Familial dysautonomia	2022-04-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330656	SCV004037896	uncertain significance	not specified	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: ELP1 c.947C>T (p.Pro316Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 282846 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ELP1 causing Familial Dysautonomia (0.00022 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.947C>T in individuals affected with Familial Dysautonomia and no experimental evidence demonstrating its impact on protein function have been reported. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000302687	SCV001452214	uncertain significance	Familial dysautonomia	2020-01-17	no assertion criteria provided	clinical testing