ClinVar Miner

Submissions for variant NM_003640.5(ELP1):c.3869A>G (p.Asn1290Ser)

gnomAD frequency: 0.00083  dbSNP: rs145319352
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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 RCV000355008 SCV000476541 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.
GeneDx RCV000757404 SCV000618672 uncertain significance not provided 2017-07-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the IKBKAP gene. The N1290S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N1290S variant is observed in 30/10398 (0.3%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N1290S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757404 SCV000885610 uncertain significance not provided 2017-06-14 criteria provided, single submitter clinical testing The p.Asn1290Ser variant (rs145319352) has not been reported in the medical literature, nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 364552). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in African populations of 0.30% (identified in 71 out of 24,036 chromosomes). The asparagine at codon 1290 is moderately conserved (Alamut software v2.9), however several species of rodent, in addition to other species of mammal, have a serine at this position, suggesting this change is evolutionary tolerated. Furthermore, computational analyses suggest this variant does not have a significant effect on IKBKAP protein structure/function (SIFT: tolerated, PolyPhen2: benign, and Mutation Taster: polymorphism). However, based on the available information, the clinical significance of the p.Asn1290Ser variant cannot be determined with certainty.
Invitae RCV000757404 SCV001004923 likely benign not provided 2024-01-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV002461118 SCV002755575 likely benign Inborn genetic diseases 2020-12-01 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.
Natera, Inc. RCV000355008 SCV001461177 uncertain significance Familial dysautonomia 2020-01-24 no assertion criteria provided clinical testing

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