Submissions for variant NM_001376.5(DYNC1H1):c.13682C>T (p.Thr4561Met)

gnomAD frequency: 0.00001  dbSNP: rs1376784009

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001112298	SCV001269947	uncertain significance	Charcot-Marie-Tooth disease axonal type 2O	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001112299	SCV001269948	uncertain significance	Autosomal dominant cerebellar ataxia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001555141	SCV001776504	uncertain significance	not provided	2021-03-24	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
New York Genome Center	RCV002265943	SCV002548887	uncertain significance	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures; Charcot-Marie-Tooth disease axonal type 2O; Intellectual disability, autosomal dominant 13	2021-08-12	criteria provided, single submitter	clinical testing	The c.13682C>T (p.Thr4561Met) variant identified in the DYNC1H1 gene substitutes a conserved Threonine for Methionine at amino acid 4561/4647(exon 76/78). This variant is found with low frequency in gnomAD(v3.1.1)(1 heterozygote, 0 homozygote; allele frequency: 6.57e-6) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.033) and Benign (REVEL;score:0.1099) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:882555), and to our current knowledge has not been reported in affected individuals in the literature. The p.Thr4561 residue is not within a mapped domain of DYNC1H1 (UniProtKB:Q14204). Given the lack of compelling evidence for its pathogenicity, the c.13682C>T (p.Thr4561Met) variant identified in the DYNC1H1 gene is reported as a Variant of Uncertain Significance.
Ambry Genetics	RCV002379652	SCV002702219	uncertain significance	Inborn genetic diseases	2017-12-18	criteria provided, single submitter	clinical testing	The p.T4561M variant (also known as c.13682C>T), located in coding exon 76 of the DYNC1H1 gene, results from a C to T substitution at nucleotide position 13682. The threonine at codon 4561 is replaced by methionine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001112298	SCV003459097	uncertain significance	Charcot-Marie-Tooth disease axonal type 2O	2022-12-17	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.003%). 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. 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 882555). This variant has not been reported in the literature in individuals affected with DYNC1H1-related conditions. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 4561 of the DYNC1H1 protein (p.Thr4561Met).