Submissions for variant NM_001377.3(DYNC2H1):c.1289G>A (p.Arg430His)

gnomAD frequency: 0.00006  dbSNP: rs770380730

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000515952	SCV001484649	uncertain significance	Jeune thoracic dystrophy	2022-07-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 430 of the DYNC2H1 protein (p.Arg430His). This variant is present in population databases (rs770380730, gnomAD 0.04%). This missense change has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 29068549). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 446591). 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 not expected to disrupt DYNC2H1 protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488647	SCV004242011	uncertain significance	not specified	2023-12-08	criteria provided, single submitter	clinical testing	Variant summary: DYNC2H1 c.1289G>A (p.Arg430His) results in a non-conservative amino acid change located in the Dynein heavy chain, tail domain (IPR013594) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.1e-05 in 220506 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia (9.1e-05 vs 0.0025), allowing no conclusion about variant significance. c.1289G>A has been reported in the literature in an individual affected with asphyxiating thoracic dystrophy (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). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Dan Cohn Lab, University Of California Los Angeles	RCV000515952	SCV000611986	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515952	SCV001479576	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research