Submissions for variant NM_001377.3(DYNC2H1):c.8012T>C (p.Met2671Thr)

gnomAD frequency: 0.00006  dbSNP: rs1196317554

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001541195	SCV001759164	likely pathogenic	not provided	2023-01-27	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29068549, 31974414, 28518170, 34529350)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000515910	SCV004277728	pathogenic	Jeune thoracic dystrophy	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2671 of the DYNC2H1 protein (p.Met2671Thr). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with short-rib polydactyly syndrome, also known as asphyxiating thoracic dystrophy (PMID: 28518170, 29068549, 34529350). 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: 446558). 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) 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701583	SCV005203877	likely pathogenic	Asphyxiating thoracic dystrophy 3	2024-07-02	criteria provided, single submitter	clinical testing	Variant summary: DYNC2H1 c.8012T>C (p.Met2671Thr) results in a non-conservative amino acid change located in the Dynein heavy chain, AAA module D4 domain (IPR024317) 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 8.1e-06 in 248082 control chromosomes. c.8012T>C has been reported in the literature in multiple compound heterozygous individuals affected with Short-rib thoracic dysplasia, including asphyxiating thoracic dystrophy (e.g. Silveira_2021, Vora_2017, Zhang_2018). 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: 34529350, 28518170, 29068549). ClinVar contains an entry for this variant (Variation ID: 446558). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Dan Cohn Lab, University Of California Los Angeles	RCV000515910	SCV000611937	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515910	SCV001479890	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research