Submissions for variant NM_001377.3(DYNC2H1):c.7966C>T (p.Arg2656Cys)

gnomAD frequency: 0.00003  dbSNP: rs371214841

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230526	SCV003929128	uncertain significance	not specified	2023-04-26	criteria provided, single submitter	clinical testing	Variant summary: DYNC2H1 c.7966C>T (p.Arg2656Cys) results in a non-conservative amino acid change located in the Dynein heavy chain, AAA module D4 (IPR024317) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 248576 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7966C>T has been reported in the literature in at least one compound heterozygous individual affected with Short-rib thoracic dysplasia (Zhang_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29068549). One ClinVar submitter has assessed the variant since 2014 without evidence for independent evaluation: the variant was classified as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV003748236	SCV004559062	likely pathogenic	Jeune thoracic dystrophy	2023-07-28	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYNC2H1 protein function. ClinVar contains an entry for this variant (Variation ID: 446533). This missense change has been observed in individual(s) with short-rib polydactyly syndrome (PMID: 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs371214841, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2656 of the DYNC2H1 protein (p.Arg2656Cys).
Dan Cohn Lab, University Of California Los Angeles	RCV001291277	SCV000611905	pathogenic	Asphyxiating thoracic dystrophy 3	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291277	SCV001479718	likely pathogenic	Asphyxiating thoracic dystrophy 3		no assertion criteria provided	research