Submissions for variant NM_001376.5(DYNC1H1):c.751C>T (p.Arg251Cys)

dbSNP: rs879253979

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414974	SCV000492853	likely pathogenic	Myopathy; Pes cavus; Hammertoe; Distal lower limb amyotrophy	2015-05-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000512659	SCV000608712	uncertain significance	not provided	2016-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV000649558	SCV000771387	pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2023-07-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 251 of the DYNC1H1 protein (p.Arg251Cys). For these reasons, this variant has been classified as Pathogenic. 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: 26392352; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 374099). This missense change has been observed in individual(s) with spinal muscular atrophy with lower extremity predominance (PMID: 30122514). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV001266345	SCV001444519	likely pathogenic	Inborn genetic diseases	2020-10-22	criteria provided, single submitter	clinical testing	The c.751C>T (p.R251C) alteration is located in coding exon 4 of the DYNC1H1 gene. This alteration results from a C to T substitution at nucleotide position 751, causing the arginine (R) at amino acid position 251 to be replaced by a cysteine (C). Based on data from the Genome Aggregation Database (gnomAD), the DYNC1H1 c.751C>T alteration was not observed, with coverage at this position. This alteration has been reported to occur de novo in 4 unrelated patients with SMALED. All patients presented with early onset lower limb muscle weakness and wasting, later onset upper extremity weakness, and mild brain MRI abnormalities. Cognitive function was variable (Chan, 2018). This alteration was also reported in a patient with an unspecified abnormality of the nervous system (Retterer, 2016). A patient with peripheral neuropathy was reported to have a different alteration at the same codon, c.752G>A (p.R251H), by Antoniadi, et al. (2015). The p.R251 amino acid is conserved in available vertebrate species. The in silico prediction for the p.R251C alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000512659	SCV001807523	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000512659	SCV001917698	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000512659	SCV001953619	pathogenic	not provided		no assertion criteria provided	clinical testing
Département de Neurologie, Hospices Civils de Lyon	RCV003325406	SCV003836497	likely pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	2023-02-24	no assertion criteria provided	clinical testing