Submissions for variant NM_001377.3(DYNC2H1):c.5087C>T (p.Thr1696Met)

gnomAD frequency: 0.00002  dbSNP: rs751030969

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000515916	SCV003469599	likely pathogenic	Jeune thoracic dystrophy	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1696 of the DYNC2H1 protein (p.Thr1696Met). This variant is present in population databases (rs751030969, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of short-rib thoracic dysplasia with or without polydactyly (PMID: 29068549, 29096039). ClinVar contains an entry for this variant (Variation ID: 446616). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230527	SCV003929129	uncertain significance	not specified	2023-04-27	criteria provided, single submitter	clinical testing	Variant summary: DYNC2H1 c.5087C>T (p.Thr1696Met) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) and hydrolytic ATP-binding dynein motor region (IPR035699) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 246386 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5087C>T has been reported in the literature in at least two compound heterozygous individuals affected with Short-rib thoracic dysplasia (e.g., Zhang_2018, Stals_2018). 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: 29096039, 29068549). Two ClinVar submitters (evaluation after 2014) have classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as as VUS-possibly pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV003326448	SCV004033154	likely pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	DYNC2H1: PM1, PM2, PP4:Moderate, PP3
Dan Cohn Lab, University Of California Los Angeles	RCV000515916	SCV000612020	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515916	SCV001479897	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research