Submissions for variant NM_001377.3(DYNC2H1):c.6910G>A (p.Ala2304Thr)

dbSNP: rs747348765

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521573	SCV000617826	likely pathogenic	not provided	2023-09-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23456818, 29068549, 33875766, 29947050)
Rare Disease Group, Clinical Genetics, Karolinska Institutet	RCV000754936	SCV000788361	uncertain significance	Jeune thoracic dystrophy	2018-05-01	criteria provided, single submitter	research
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000521573	SCV001449813	likely pathogenic	not provided	2015-06-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003419889	SCV004117234	likely pathogenic	DYNC2H1-related condition	2024-02-02	criteria provided, single submitter	clinical testing	The DYNC2H1 c.6910G>A variant is predicted to result in the amino acid substitution p.Ala2304Thr. This variant was reported in an individual with asphyxiating thoracic dystrophy (Table 2, Schmidts et al. 2013. PubMed ID: 23456818), and individuals with short-rib polydactyly syndrome (neonate in Table S2, Zhang et al. 2018. PubMed ID: 29068549; fetus in Table 2, Daum et al. 2019. PubMed ID: 29947050; Hammarsjö et al. 2021. PubMed ID: 33875766). This variant is reported in 0.070% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as likely pathogenic.
Invitae	RCV000754936	SCV004291014	pathogenic	Jeune thoracic dystrophy	2024-01-21	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 2304 of the DYNC2H1 protein (p.Ala2304Thr). This variant is present in population databases (rs747348765, gnomAD 0.07%). This missense change has been observed in individuals with clinical features of short-rib thoracic dysplasia with or without polydactyly (PMID: 23456818, 29068549). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 446539). 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 with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Dan Cohn Lab, University Of California Los Angeles	RCV001291177	SCV000611914	pathogenic	Asphyxiating thoracic dystrophy 3	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV001291177	SCV001479595	likely pathogenic	Asphyxiating thoracic dystrophy 3		no assertion criteria provided	research