Submissions for variant NM_003640.5(ELP1):c.2908T>A (p.Leu970Met)

dbSNP: rs180931232

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001248536	SCV001422030	uncertain significance	not provided	2021-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with methionine at codon 970 of the ELP1 protein (p.Leu970Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is present in population databases (rs180931232, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with ELP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844278	SCV002103703	uncertain significance	not specified	2022-02-23	criteria provided, single submitter	clinical testing	Variant summary: IKBKAP c.2908T>A (p.Leu970Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251272 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2908T>A in individuals affected with Familial Dysautonomia and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV001844278	SCV002755862	uncertain significance	not specified	2021-05-27	criteria provided, single submitter	clinical testing	The p.L970M variant (also known as c.2908T>A), located in coding exon 26 of the IKBKAP gene, results from a T to A substitution at nucleotide position 2908. The leucine at codon 970 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002499435	SCV002791590	uncertain significance	Medulloblastoma; Familial dysautonomia	2022-01-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001830041	SCV002082059	uncertain significance	Familial dysautonomia	2020-05-05	no assertion criteria provided	clinical testing