ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.17048C>T (p.Ala5683Val) (rs761829162)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523993 SCV000621972 uncertain significance not provided 2017-11-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the NEB gene. The c.17048 C>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.17048 C>T variant is observed in 4/22470 (0.02%) alleles from individuals of African background (Lek et al., 2016). Several in-silico splice prediction models predict that c.17048 C>T creates a cryptic donor site for intron 108 upstream of the natural donor site which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. If the c.17048 C>T variant does not affect splicing, it will result in the A5683V missense change. The A5683V 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; and in silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000685959 SCV000813460 uncertain significance Nemaline myopathy 2 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 5683 of the NEB protein (p.Ala5683Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs761829162, ExAC 0.02%). This variant has not been reported in the literature in individuals with NEB-related disease. ClinVar contains an entry for this variant (Variation ID: 453111). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Illumina Clinical Services Laboratory,Illumina RCV000685959 SCV001292071 uncertain significance Nemaline myopathy 2 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.
Natera, Inc. RCV000685959 SCV001455269 uncertain significance Nemaline myopathy 2 2020-09-16 no assertion criteria provided clinical testing

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