Submissions for variant NM_001376.5(DYNC1H1):c.791G>A (p.Arg264Gln)

dbSNP: rs713993043

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000726892	SCV001247021	pathogenic	not provided	2020-06-01	criteria provided, single submitter	clinical testing
Invitae	RCV001302580	SCV001491794	pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2023-03-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg264 amino acid residue in DYNC1H1. Other variant(s) that disrupt this residue have been observed in individuals with DYNC1H1-related conditions (PMID: 25512093), which suggests that this may be a clinically significant amino acid residue. 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 DYNC1H1 protein function. ClinVar contains an entry for this variant (Variation ID: 210883). This missense change has been observed in individual(s) with spinal muscular atrophy (PMID: 25609763). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 264 of the DYNC1H1 protein (p.Arg264Gln).
GeneDx	RCV000726892	SCV002031019	pathogenic	not provided	2022-10-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25609763, 26100331, 25512093, 32656949)
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273981	SCV002559113	likely pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726892	SCV003829181	likely pathogenic	not provided	2023-12-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV003985080	SCV004801415	likely pathogenic	DYNC1H1-related neurological disorders	2023-10-24	criteria provided, single submitter	clinical testing	The DYNC1H1 c.791G>A, p.(Arg264Gln) missense variant has been identified in an individual with a phenotype consistent with DYNC1H1-related neurological disorders who demonstrated lower limb malformations, compromised hand function, fine motor difficulties and a brain malformation resembling polymicrogyria by MRI (Scoto et al. 2015). Additionally, a different amino acid substitution at the same codon, p.(Arg264Leu), has been reported in an individual with a phenotype consistent with DYNC1H1-related neurological disorders (Peeters et al. 2015). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest this variant may impact the gene or gene product. The variant was identified in a de novo state in the proband. Based on the available evidence, the c.791G>A, p.(Arg264Gln) variant is classified as likely pathogenic for DYNC1H1-related neurological disorders.
Genetic Services Laboratory, University of Chicago	RCV000193618	SCV000247224	uncertain significance	not specified	2015-06-08	flagged submission	clinical testing
Eurofins Ntd Llc (ga)	RCV000726892	SCV000703933	uncertain significance	not provided	2018-05-01	flagged submission	clinical testing
Inherited Neuropathy Consortium	RCV000789731	SCV000929108	uncertain significance	Neuronopathy, distal hereditary motor, autosomal dominant		flagged submission	literature only
Inherited Neuropathy Consortium Ii, University Of Miami	RCV001302580	SCV004174347	uncertain significance	Charcot-Marie-Tooth disease axonal type 2O	2016-01-06	flagged submission	literature only