Submissions for variant NM_001377.3(DYNC2H1):c.5983G>A (p.Ala1995Thr)

gnomAD frequency: 0.00011  dbSNP: rs552436294

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483501	SCV000566908	pathogenic	not provided	2023-01-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31589614, 29068549, 32494556)
Fulgent Genetics, Fulgent Genetics	RCV001291051	SCV002799129	likely pathogenic	Asphyxiating thoracic dystrophy 3	2024-01-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000515935	SCV003786064	pathogenic	Jeune thoracic dystrophy	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1995 of the DYNC2H1 protein (p.Ala1995Thr). This variant is present in population databases (rs552436294, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of short-rib polydactyly syndrome (PMID: 29068549, 32494556). 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: 419236). Invitae Evidence 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 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. For these reasons, this variant has been classified as Pathogenic.
Dan Cohn Lab, University Of California Los Angeles	RCV001291051	SCV000611946	pathogenic	Asphyxiating thoracic dystrophy 3	2017-06-01	no assertion criteria provided	research
Dan Cohn Lab, University Of California Los Angeles	RCV000515935	SCV000611980	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291051	SCV001479398	likely pathogenic	Asphyxiating thoracic dystrophy 3		no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515935	SCV001479570	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003401520	SCV004106044	pathogenic	DYNC2H1-related disorder	2023-12-06	no assertion criteria provided	clinical testing	The DYNC2H1 c.5983G>A variant is predicted to result in the amino acid substitution p.Ala1995Thr. This variant was reported in at least four unrelated cases of short rib-polydactyly syndrome, type 3 (Table S2, Zhang et al. 2018. PubMed ID: 29068549; Geng et al. 2020. PubMed ID: 32494556). A different substitution affecting the same amino acid (p.Ala1995Val) was also reported in patients with short rib-polydactyly syndrome (Table S2, Zhang et al. 2018. PubMed ID: 29068549). This variant is reported in 0.0088% of alleles in individuals of Latino descent in gnomAD. At PreventionGenetics, we have observed this variant in an individual tested for short rib skeletal dysplasia. This variant is interpreted as pathogenic.