ClinVar Miner

Submissions for variant NM_001376.5(DYNC1H1):c.13088A>C (p.Lys4363Thr) (rs141925609)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230711 SCV000287106 uncertain significance Charcot-Marie-Tooth disease, axonal, type 2O 2020-06-22 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 4363 of the DYNC1H1 protein (p.Lys4363Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is present in population databases (rs141925609, ExAC 0.03%). This variant has been observed in an individual with autism; however, in that individual, a de novo variant in a different gene was also observed, making the contribution of the DYNC1H1 variant unclear (PMID: 30504930). ClinVar contains an entry for this variant (Variation ID: 238994). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, 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. 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.
GeneDx RCV001705255 SCV000726104 likely benign not provided 2019-03-01 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30504930, 31981491)
Illumina Clinical Services Laboratory,Illumina RCV001112195 SCV001269836 likely benign Autosomal dominant cerebellar ataxia 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000230711 SCV001273129 likely benign Charcot-Marie-Tooth disease, axonal, type 2O 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Genesis Genome Database RCV000856991 SCV000999559 uncertain significance Charcot-Marie-Tooth disease 2019-08-14 no assertion criteria provided research
University of Washington Center for Mendelian Genomics, University of Washington RCV001291385 SCV001479859 likely pathogenic Autism spectrum disorder no assertion criteria provided research

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