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

dbSNP: rs879253979

Total submissions: 10

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000649558	SCV000771387	pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2024-05-02	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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 374099). 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 with a positive predictive value of 95%. 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. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266345	SCV001444519	pathogenic	Inborn genetic diseases	2024-02-08	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). 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 spinal muscular atrophy (Chan, 2018; Fernández Perrone, 2022). This alteration was also reported in a patient with an unspecified abnormality of the nervous system (Retterer, 2016). Two other alterations at the same codon, c.752G>A (p.R251H) and c.752G>T (p.R251L), have been detected in patients with features consistent with DYNC1H1-related neurologic disorders (Antoniadi, 2015; Derksen, 2021). The p.R251 amino acid is 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 the p.R251C alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	RCV004719809	SCV005324728	likely pathogenic	Dyneinopathy	2025-02-10	criteria provided, single submitter	research	This variant is absent from gnomAD v4.0 (adequate coverage >20X confirmed). PM1 Not Met: pathogenic variants are distributed throughout the protein. Arginine (R) at position 251 in DYNC1H1 is a highly conserved amino acid residue. PP3 Not Met: Revel score is 0.552. PM5_Met: Multiple missense changes affecting the same amino acid are reported to be pathogenic (PMID:26392352, PMID:30122514): 751C>A (p.Arg251Ser), c.751C>T (p.Arg251Cys), c.751C>G (p.Arg251Gly) and c.752G>A (p.Arg251His). PS2 Met: 2.5 points awarded for 5 unrelated probands with a phenotype consistent with the DYNC1H1 gene but not highly specific and de novo heterozygous observations of the DYNC1H1 c.751C>T(p.Arg251Cys) variant (PMID:30122514, PMID:35606327). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000649558	SCV005885911	pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2025-02-19	criteria provided, single submitter	clinical testing	Variant summary: DYNC1H1 c.751C>T (p.Arg251Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251334 control chromosomes. c.751C>T has been reported in the literature as a de novo occurrence in individuals affected with spinal muscular atrophy with lower extremity predominance (examples: Perrone_2022, Chan_2018). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35606327, 30122514). ClinVar contains an entry for this variant (Variation ID: 374099). Based on the evidence outlined above, the variant was classified as 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