Submissions for variant NM_001377.3(DYNC2H1):c.5984C>T (p.Ala1995Val)

dbSNP: rs963717773

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000516046	SCV001375078	uncertain significance	Jeune thoracic dystrophy	2022-09-21	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1995 of the DYNC2H1 protein (p.Ala1995Val). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446619). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYNC2H1 protein function. This variant disrupts the p.Ala1995 amino acid residue in DYNC2H1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29068549). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV003332188	SCV004040189	pathogenic	not provided	2023-10-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37007936, 29068549, 33777089, 36307859, 26582918, 24077912)
Dan Cohn Lab, University Of California Los Angeles	RCV000516046	SCV000612024	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000516046	SCV001479409	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research