Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Fulgent Genetics, |
RCV002499719 | SCV002780646 | uncertain significance | Holocarboxylase synthetase deficiency | 2022-03-15 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV002499719 | SCV003519211 | uncertain significance | Holocarboxylase synthetase deficiency | 2022-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 472 of the HLCS protein (p.Ala472Gly). This variant is present in population databases (rs767190021, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with HLCS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1050466). 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 HLCS protein function. 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. |
Department of Pathology and Laboratory Medicine, |
RCV001357933 | SCV001553540 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The HLCS p.Ala619Gly variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs767190021) and in control databases in 5 of 251440 chromosomes at a frequency of 0.00001989 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 1 of 6138 chromosomes (freq: 0.000163), Ashkenazi Jewish in 1 of 10080 chromosomes (freq: 0.000099), Latino in 1 of 34590 chromosomes (freq: 0.000029) and European (non-Finnish) in 2 of 113724 chromosomes (freq: 0.000018), but was not observed in the African, East Asian, European (Finnish), or South Asian populations. The p.Ala619 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. 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. This variant is classified as a variant of uncertain significance. |