Submissions for variant NM_001376.5(DYNC1H1):c.4700G>A (p.Arg1567Gln)

dbSNP: rs797044901

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190726	SCV000244167	pathogenic	Inborn genetic diseases	2022-08-25	criteria provided, single submitter	clinical testing	The c.4700G>A (p.R1567Q) alteration is located in exon 22 (coding exon 22) of the DYNC1H1 gene. This alteration results from a G to A substitution at nucleotide position 4700, causing the arginine (R) at amino acid position 1567 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported as de novo in multiple individuals with intellectual disability/developmental delay, brain MRI abnormalities, and additional variable features consistent with DYNC1H1-related neurologic disorders (Poirier, 2013; Srivastava, 2014; Demos, 2019; Järvelä, 2021; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). In vitro assays examining the effect of DYNC1H1 mutations on dynein microtubule motor motility demonstrated that, compared to the wild-type, the p.R1567Q alteration reduced the distance traveled by dynein–dynactin–BICD2N complexes before pausing or detaching from the microtubule (Hoang, 2017). Another functional study demonstrated that the p.R1567Q alteration reduced cytoplasmic localization of DYNC1H1 and inhibited binding interaction with dynactin 1 compared to the wild-type (Pijuan, 2021). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000236127	SCV000293268	pathogenic	not provided	2020-08-04	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect by reducing the run length of the dyneindynactinBICD2N complexes (Hoang et al., 2017); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25356970, 23603762, 25512093, 28196890, 31164858)
Center for Statistical Genetics, Columbia University	RCV001261370	SCV001438280	pathogenic	Intellectual disability	2020-10-16	criteria provided, single submitter	research
Genetic Services Laboratory, University of Chicago	RCV000236127	SCV002072067	pathogenic	not provided	2017-07-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852534	SCV002235597	pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2023-06-11	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects DYNC1H1 function (PMID: 28196890). 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: 208709). This missense change has been observed in individual(s) with DYNC1H1-related conditions (PMID: 23603762, 31164858). 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 1567 of the DYNC1H1 protein (p.Arg1567Gln).
Revvity Omics, Revvity	RCV000236127	SCV003823345	pathogenic	not provided	2021-12-28	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796088	SCV005415984	pathogenic	Intellectual disability, autosomal dominant 13		criteria provided, single submitter	clinical testing	PM2_Supporting+PP2+PS3_Moderate+PS2+PS4_Moderate+PP4
Inherited Neuropathy Consortium Ii, University Of Miami	RCV001852534	SCV004174802	uncertain significance	Charcot-Marie-Tooth disease axonal type 2O	2016-01-06	no assertion criteria provided	literature only