Submissions for variant NM_001377.3(DYNC2H1):c.12410C>G (p.Pro4137Arg)

gnomAD frequency: 0.00003  dbSNP: rs761765709

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000486569	SCV000232861	uncertain significance	not provided	2015-05-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228783	SCV000285823	pathogenic	Jeune thoracic dystrophy	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 4144 of the DYNC2H1 protein (p.Pro4144Arg). This variant is present in population databases (rs761765709, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of asphyxiating thoracic dystrophy (PMID: 29068549, 30655312, 30773290). 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: 198962). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000486569	SCV000574151	likely pathogenic	not provided	2023-01-03	criteria provided, single submitter	clinical testing	Not observed at a 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: 29068549, 30773290, 30655312)
Illumina Laboratory Services, Illumina	RCV001105946	SCV001262970	uncertain significance	Asphyxiating thoracic dystrophy 3	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586603	SCV005077567	uncertain significance	not specified	2024-04-03	criteria provided, single submitter	clinical testing	Variant summary: DYNC2H1 c.12431C>G (p.Pro4144Arg) results in a non-conservative amino acid change located in the Dynein heavy chain, C-terminal domain (IPR041228) 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 8e-06 in 248572 control chromosomes (gnomAD). c.12431C>G has been reported in the literature in individuals affected with Short-rib thoracic dysplasia (Zhang_2018, Connaughton_2019, Mann_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29068549, 30773290, 30655312). ClinVar contains an entry for this variant (Variation ID: 198962). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001105946	SCV005680495	likely pathogenic	Asphyxiating thoracic dystrophy 3	2024-04-06	criteria provided, single submitter	clinical testing
Dan Cohn Lab, University Of California Los Angeles	RCV000228783	SCV000611938	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000228783	SCV001479367	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research