ClinVar Genomic variation as it relates to human health

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.

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.

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.

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.