Submissions for variant NM_001377.3(DYNC2H1):c.12896G>A (p.Gly4299Glu)

gnomAD frequency: 0.00001  dbSNP: rs770569272

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001316479	SCV001507103	uncertain significance	Jeune thoracic dystrophy	2021-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with glutamic acid at codon 4306 of the DYNC2H1 protein (p.Gly4306Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs770569272, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of DYNC2H1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 446681). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004701586	SCV005205523	uncertain significance	not specified	2024-06-24	criteria provided, single submitter	clinical testing	Variant summary: DYNC2H1 c.12917G>A (p.Gly4306Glu) 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 248780 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.12917G>A has been reported in the literature in at least one individual affected with Short-rib thoracic dysplasia who was heterozygous for the variant (Zhang_2018). However, a second variant was not identified in this individual. These report(s) do not provide unequivocal conclusions about association of the variant with Short-rib thoracic dysplasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446681). Based on the evidence outlined above, the variant was classified as uncertain significance.
Dan Cohn Lab, University Of California Los Angeles	RCV000515978	SCV000612112	uncertain significance	Short-rib thoracic dysplasia 6 with or without polydactyly	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000515978	SCV001479544	likely pathogenic	Short-rib thoracic dysplasia 6 with or without polydactyly		no assertion criteria provided	research