Submissions for variant NM_001377.3(DYNC2H1):c.11263A>G (p.Met3755Val)

gnomAD frequency: 0.00105  dbSNP: rs137853026

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726973	SCV000616702	uncertain significance	not provided	2017-08-18	criteria provided, single submitter	clinical testing	The M3762V variant has been published in the homozygous state in two children affected with skeletal dysplasia born to consanguineous parents; however, these children were also homozygous for another variant in the DYNC2H1 gene (Dagoneau et al., 2009). The M3762V variant is observed in 35/9648 (0.36%) alleles from individuals of African background in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M3762V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.
Eurofins Ntd Llc (ga)	RCV000726973	SCV000704592	uncertain significance	not provided	2016-12-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000006874	SCV001474293	uncertain significance	Asphyxiating thoracic dystrophy 3	2019-10-31	criteria provided, single submitter	clinical testing	The DYNC2H1 c.11284A>G; p.Met3762Val variant (rs137853026) is reported in the literature in the homozygous state in multiple individuals affected with asphyxiating thoracic dystrophy, although some of these individuals also carry other variants in cis (Baujat 2013, Dagoneau 2009, Zhang 2018). This variant is reported] in ClinVar (Variation ID: 6501), and is found in the African population with an allele frequency of 0.32% (78/24098 alleles) in the Genome Aggregation Database. The methionine at codon 3762 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the limited clinical and functional data, the significance of the p.Met3762Val variant is uncertain at this time. References: Baujat G et al. Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families. J Med Genet. 2013 Feb;50(2):91-8. Dagoneau N et al. DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. Am J Hum Genet. 2009 May;84(5):706-11. Zhang W et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018 Jan;39(1):152-166.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000516063	SCV002380718	likely benign	Jeune thoracic dystrophy	2024-11-19	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000006874	SCV002573255	uncertain significance	Asphyxiating thoracic dystrophy 3	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.039%). The evidence of pathogenicity is insufficient at this time. This variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000006874	SCV002769048	uncertain significance	Asphyxiating thoracic dystrophy 3	2024-09-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with short-rib thoracic dysplasia 3 with or without polydactyly (MIM#613091). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (153 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated AAA6 region (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported by seven clinical laboratories as a VUS, and one as likely benign (ClinVar). It has also been reported as compound heterozygous in an individual with asphyxiating thoracic dystrophy (ATD), a fetus with skeletal dysplasia, and a fetus with ultrasound findings of short femur and humerus lengths (PMID: 29068549, Johnson, K. and Eason, J. (2018), ClinVar - personal communication). In addition, this variant has been reported as homozygous in two individuals with ATD, including one who also had a CEP57 variant and a composite phenotype (PMIDs: 23339108, 31943948). It has also been reported as homozygous in an individual with severe global developmental delay, axial hypotonia and limb spasticity, who is also homozygous for a SOD1 variant that was regarded as the genetic diagnosis (PMID: 34788402), and an individual who does not have DYNC2H1-related symptoms (ClinVar - personal communication). Furthermore, this variant has been reported in cis with p.(Met1991Leu) (PMIDs: 19442771, 33875766); however, these reports were not considered for the classification of this variant. (I) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated within an extended consanguineous family, however as another variant is present in cis, the evidence is inconclusive (PMID: 19442771). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004766983	SCV005381151	uncertain significance	not specified	2024-08-13	criteria provided, single submitter	clinical testing	Variant summary: DYNC2H1 c.11284A>G (p.Met3762Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 246608 control chromosomes, predominantly at a frequency of 0.0036 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.44 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYNC2H1 causing Short-rib thoracic dysplasia phenotype (0.0025), however no homozygotes were present. c.11284A>G has been reported in the literature in individuals affected with Short-rib thoracic dysplasia, including in a homozygous patient without any other reported variants (Baujat_2013) and in three homozygous patients who also carried other possibly causitive homozygous or heterozygous DYNC2H1 variants (Hammarsjo_2021, Dagoneau_2009, Zhang_2019). Additionally, the variant was reported in a patient with complex phenotype in a homozygous patient who also carried homozygous CEP57 c.915_925dup (p.Leu309Profs*9) who had features of both DYNC2H1 and CEP57-related disease. The current clinical evidence is not sufficient to prove the causitive relationship of the variant to disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 6501). Based on the evidence outlined above, the variant was classified as uncertain significance.
OMIM	RCV000006874	SCV000027070	pathogenic	Asphyxiating thoracic dystrophy 3	2009-05-01	flagged submission	literature only
Dan Cohn Lab, University Of California Los Angeles	RCV000516063	SCV000611970	pathogenic	Jeune thoracic dystrophy	2017-06-01	flagged submission	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000516063	SCV001479560	likely pathogenic	Jeune thoracic dystrophy		flagged submission	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000726973	SCV001797972	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000726973	SCV001959465	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000726973	SCV001965742	uncertain significance	not provided		no assertion criteria provided	clinical testing