Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000798585 | SCV000938208 | likely benign | Charcot-Marie-Tooth disease axonal type 2O | 2024-02-01 | criteria provided, single submitter | clinical testing | |
Molecular Genetics, |
RCV002225118 | SCV002503651 | uncertain significance | Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures | 2020-11-20 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace glycine with alanine at codon 3657 of the DYNC1H1 protein (p.(Gly3657Ala)). The glycine residue is invariant across species (100 vertebrates, UCSC), and is located in the AAA 5 domain in the ATP-binding dynein motor region. There is a moderate physicochemical difference between glycine and alanine. The gene is highly constrained for missense variants (gnomAD v2.1). The variant is present in a large population cohort at a frequency of 0.002% (rs761427653, 5/251,400 alleles, 0 homozygotes in gnomAD v2.1), but is not present in a healthy control cohort (0/60,146 alleles in gnomAD v2.1). The variant has been identified in at least three individuals undergoing genetic testing for a neuropathy, but with inconsistent phenotypes (Invitae). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). A missense variant in an adjacent amino acid (p.Gly3658Glu) has been identified in a case with a malformation of cortical development (PMID: 27331017). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE . Following criteria are met: PP2, PP3. |
Ambry Genetics | RCV002537999 | SCV003597578 | uncertain significance | Inborn genetic diseases | 2022-01-05 | criteria provided, single submitter | clinical testing | The c.10970G>C (p.G3657A) alteration is located in exon 58 (coding exon 58) of the DYNC1H1 gene. This alteration results from a G to C substitution at nucleotide position 10970, causing the glycine (G) at amino acid position 3657 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
Neuberg Supratech Reference Laboratories Pvt Ltd, |
RCV003338806 | SCV004047916 | uncertain significance | Intellectual disability, autosomal dominant 13 | criteria provided, single submitter | clinical testing | The missense variant c.10970G>C (p.Gly3657Ala) in DYNC1H1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.001%) in the gnomAD and novel in 1000 genome database. It is submitted to ClinVar as Uncertain significance. The amino acid Glycine at position 3657 is changed to a Alanine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The residue is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. |