ClinVar Miner

Submissions for variant NM_003640.5(ELP1):c.3785C>T (p.Thr1262Met)

gnomAD frequency: 0.00005  dbSNP: rs199723919
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000315333 SCV000476543 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000756274 SCV000830892 uncertain significance not provided 2022-07-12 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1262 of the ELP1 protein (p.Thr1262Met). This variant is present in population databases (rs199723919, gnomAD 0.03%). 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: 364554). 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 methionine 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756274 SCV000884034 uncertain significance not provided 2018-05-14 criteria provided, single submitter clinical testing The p.Thr1262Met variant (rs199723919) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.03 percent in the European Finnish population (identified on 8 out of 25,790 chromosomes), and has been reported to the ClinVar database (Variation ID: 364554). The threonine at position 1262 is weakly conserved considering 13 species (Alamut v2.11) and computational analyses of the p.Thr1262Met variant on protein structure and function indicate a neutral effect (SIFT: tolerated, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Thr1262Met variant with certainty.
Ambry Genetics RCV004022090 SCV003530704 uncertain significance not specified 2022-11-22 criteria provided, single submitter clinical testing The c.3785C>T (p.T1262M) alteration is located in exon 35 (coding exon 34) of the IKBKAP gene. This alteration results from a C to T substitution at nucleotide position 3785, causing the threonine (T) at amino acid position 1262 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV000756274 SCV003803509 uncertain significance not provided 2022-08-12 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc. RCV000315333 SCV001461179 uncertain significance Familial dysautonomia 2020-01-17 no assertion criteria provided clinical testing

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