Submissions for variant NM_001376.5(DYNC1H1):c.752G>A (p.Arg251His)

dbSNP: rs794727634

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548783	SCV000651666	pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2022-11-01	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with autosomal dominant hereditary motor neuropathy (PMID: 26392352; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197195). 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. This variant disrupts the p.Arg251 amino acid residue in DYNC1H1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30122514). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 251 of the DYNC1H1 protein (p.Arg251His).
Ambry Genetics	RCV000623418	SCV000742400	pathogenic	Inborn genetic diseases	2024-09-20	criteria provided, single submitter	clinical testing	The c.752G>A (p.R251H) alteration is located in exon 4 (coding exon 4) of the DYNC1H1 gene. This alteration results from a G to A substitution at nucleotide position 752, causing the arginine (R) at amino acid position 251 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with DYNC1H1-related neurologic disorders (Abolhassani, 2024; Dabhade, 2023). This variant was identified in one or more individuals with features consistent with DYNC1H1-related neurologic disorders (Antoniadi, 2015; Saleh, 2021; Ek, 2023; Fernández-Eulate, 2023; Ambry internal data; external communication) and segregated with disease in at least one family (external communication). 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). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001836743	SCV000992237	pathogenic	Peripheral neuropathy	2021-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000178163	SCV001769846	pathogenic	not provided	2020-10-30	criteria provided, single submitter	clinical testing	Reported as likely pathogenic in an individual with hereditary motor neuropathy (HMN); however phenotypic details and segregation data were not provided (Antoniadi et al., 2015); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26392352, 30122514)
Mendelics	RCV002247590	SCV002516315	likely pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	2022-05-04	criteria provided, single submitter	clinical testing
CHU Sainte-Justine Research Center, University of Montreal	RCV002247590	SCV003761476	pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	2022-03-24	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000548783	SCV003807943	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2022-09-02	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM2 moderated, PM5 moderated, PP2 supporting
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000548783	SCV003932314	pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2023-02-10	criteria provided, single submitter	clinical testing	PS2, PS4_Moderate, PM2, PP2, PP3
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798799	SCV005420404	likely pathogenic	Charcot-Marie-Tooth disease	2024-10-04	criteria provided, single submitter	research	PP1_Moderate,PM2,PS4,PP3,PM5
Eurofins Ntd Llc (ga)	RCV000178163	SCV000230170	uncertain significance	not provided	2014-11-23	flagged submission	clinical testing