Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001241686 | SCV001414720 | uncertain significance | Congenital myopathy with internal nuclei and atypical cores | 2024-06-11 | 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 288 of the CCDC78 protein (p.Arg288Cys). This variant is present in population databases (rs764179609, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CCDC78-related conditions. ClinVar contains an entry for this variant (Variation ID: 966902). 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 CCDC78 protein function with a positive predictive value of 80%. 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. |
| Ambry Genetics | RCV002564007 | SCV003717039 | uncertain significance | Inborn genetic diseases | 2022-11-18 | criteria provided, single submitter | clinical testing | The c.862C>T (p.R288C) alteration is located in exon 9 (coding exon 9) of the CCDC78 gene. This alteration results from a C to T substitution at nucleotide position 862, causing the arginine (R) at amino acid position 288 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Department of Pathology and Laboratory Medicine, |
RCV001355332 | SCV001550194 | likely benign | not provided | no assertion criteria provided | clinical testing | The CCDC78 p.Arg288Cys variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs764179609) and in control databases in 11 of 274772 chromosomes at a frequency of 0.00004003 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 4 of 30518 chromosomes (freq: 0.000131), European (non-Finnish) in 6 of 124768 chromosomes (freq: 0.000048) and African in 1 of 24396 chromosomes (freq: 0.000041), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. This frequency is greater than expected for autosomal dominant centronuclear myopathy 4. Although the p.Arg288 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. |