ClinVar Miner

Submissions for variant NM_001377.3(DYNC2H1):c.6047A>G (p.Tyr2016Cys) (rs200190291)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197773 SCV000254667 uncertain significance Jeune thoracic dystrophy 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 2016 of the DYNC2H1 protein (p.Tyr2016Cys). The tyrosine residue is weakly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs200190291, ExAC 0.09%). This variant has not been reported in the literature in individuals with DYNC2H1-related disease. ClinVar contains an entry for this variant (Variation ID: 216490). 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: "Benign"; Align-GVGD: "Class C15"). 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 RCV000757203 SCV000526928 uncertain significance not provided 2016-08-24 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DYNC2H1 gene. The Y2016C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project and the 1000 Genomes Project Consortium report Y2016C was observed in 11/8218 and 2/1006 alleles alleles, respectively, from individuals of European background, indicating it may be a rare benign variant in this population. The Y2016C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in a nearby residue (Ala2012Val) has been reported in the Human Gene Mutation Database in association with asphyxiating thoracic dystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. 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 RCV000757203 SCV000885345 uncertain significance not provided 2018-06-26 criteria provided, single submitter clinical testing The DYNC2H1 c.6047A>G; p.Tyr2016Cys variant (rs200190291) has been described in the compound heterozygous state in one family with recurrent early pregnancy loss and in one individual with short-rib thoracic dysplasia type IV (Qiao 2016, Zhang 2018). It is reported in ClinVar (Variation ID: 216490) and is observed in the general population at an overall frequency of 0.078% (216/276506 alleles) in the Genome Aggregation Database. The tyrosine at codon 2016 is weakly conserved, and computational algorithms (PolyPhen-2: benign, SIFT: damaging) are inconclusive on the effect of this variant on protein structure and/or function. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. Pathogenic variants in DYNC2H1 follow autosomal recessive and digenic recessive (with NEK1 variants) inheritance patterns and are associated with short-rib thoracic dysplasia 3 with or without polydactyly (MIM: 613091). [Because no other significant variants were identified in DYNC2H1 or NEK1, even if this variant is later determined to be pathogenic, this patient would be predicted to be a carrier only;] however, our analysis cannot detect variants in deep intronic or enhancer regions, so an additional pathogenic variant in these regions cannot be ruled out. References: Qiao Y et al. Whole exome sequencing in recurrent early pregnancy loss. Mol Hum Reprod. 2016 May;22(5):364-72. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166.
Dan Cohn Lab,University Of California Los Angeles RCV000516059 SCV000612127 pathogenic Type IV short rib polydactyly syndrome 2017-06-01 no assertion criteria provided research

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