Submissions for variant NM_001377.3(DYNC2H1):c.11270A>G (p.Gln3757Arg)

gnomAD frequency: 0.00003  dbSNP: rs758727391

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000516103	SCV001496486	uncertain significance	Jeune thoracic dystrophy	2022-07-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 3764 of the DYNC2H1 protein (p.Gln3764Arg). This variant is present in population databases (rs758727391, gnomAD 0.2%). This missense change has been observed in individual(s) with asphyxiating thoracic dystrophy (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446580). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001803801	SCV002049065	uncertain significance	Asphyxiating thoracic dystrophy 3	2021-10-11	criteria provided, single submitter	clinical testing	The DYNC2H1 c.11291A>G; p.Gln3764Arg variant (rs758727391) is published in the literature in a neonate with asphyxiating thoracic dystrophy who also carried another missense DYNCH2H1 variant on the opposite chromosome (Zhang 2018). The variant is reported in the ClinVar database (Variation ID: 446580) and is found in the Latino population with an allele frequency of 0.155% (53/34,282 alleles) in the Genome Aggregation Database. The glutamine at codon 3764 is highly conserved but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.555) Due to limited information, the clinical significance of the p.Gln3764Arg variant is uncertain at this time. References: Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166. PMID: 29068549.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323581	SCV004028865	uncertain significance	not specified	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: DYNC2H1 c.11291A>G (p.Gln3764Arg) results in a conservative amino acid change located in the Dynein heavy chain region D6 P-loop domain (IPR004273) of the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 248048 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia (0.00022 vs 0.0025), allowing no conclusion about variant significance. c.11291A>G has been reported in the literature in an individual diagnosed with asphyxiating thoracic dystrophy (ATD) (Zhang_2018). 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 have been ascertained in the context of this evaluation (PMID: 29068549). ClinVar contains an entry for this variant (Variation ID: 446580). Based on the evidence outlined above, the variant was classified as uncertain significance.
Dan Cohn Lab, University Of California Los Angeles	RCV000516103	SCV000611973	pathogenic	Jeune thoracic dystrophy	2017-06-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000516103	SCV001479563	likely pathogenic	Jeune thoracic dystrophy		no assertion criteria provided	research