Submissions for variant NM_001376.5(DYNC1H1):c.7072C>T (p.Arg2358Cys)

dbSNP: rs879254019

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236944	SCV000293192	likely pathogenic	not provided	2015-09-24	criteria provided, single submitter	clinical testing	The R2358C variant in the DYNC1H1 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The R2358C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R2358C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the AAA2 ring of the motor domain, that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The R2358C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Ambry Genetics	RCV002365226	SCV002662167	uncertain significance	Inborn genetic diseases	2019-10-07	criteria provided, single submitter	clinical testing	The p.R2358C variant (also known as c.7072C>T), located in coding exon 35 of the DYNC1H1 gene, results from a C to T substitution at nucleotide position 7072. The arginine at codon 2358 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV002519822	SCV003334099	uncertain significance	Charcot-Marie-Tooth disease axonal type 2O	2022-08-23	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 245963). This variant has not been reported in the literature in individuals affected with DYNC1H1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2358 of the DYNC1H1 protein (p.Arg2358Cys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155135	SCV003844704	uncertain significance	not specified	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: DYNC1H1 c.7072C>T (p.Arg2358Cys) results in a non-conservative amino acid change located in the AAA+ ATPase domain of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.7072C>T in individuals affected with DYNC1H1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.