Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000804177 | SCV000944073 | uncertain significance | Neuronal ceroid lipofuscinosis | 2021-08-27 | criteria provided, single submitter | clinical testing | This sequence change replaces serine with leucine at codon 157 of the CTSD protein (p.Ser157Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs587779409, ExAC 0.006%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 24767253). ClinVar contains an entry for this variant (Variation ID: 100732). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
Illumina Laboratory Services, |
RCV000087098 | SCV001263717 | uncertain significance | Neuronal ceroid lipofuscinosis 10 | 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. |
Ambry Genetics | RCV002336243 | SCV002640053 | uncertain significance | Inborn genetic diseases | 2018-01-29 | criteria provided, single submitter | clinical testing | The p.S157L variant (also known as c.470C>T), located in coding exon 4 of the CTSD gene, results from a C to T substitution at nucleotide position 470. The serine at codon 157 is replaced by leucine, an amino acid with dissimilar properties. This alteration was reported in a kid with high suspicion index of lysosomal storage disease (Fernández-Marmiesse A et al. Orphanet J Rare Dis, 2014 Apr;9:59). 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV003330432 | SCV004038018 | uncertain significance | not specified | 2023-08-02 | criteria provided, single submitter | clinical testing | Variant summary: CTSD c.470C>T (p.Ser157Leu) results in a non-conservative amino acid change located in the Peptidase family A1 domain (IPR033121) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. As the variant impacts the last nucleotide of exon 4 adjacent to the canonical 5'-splicing donor site, 2/4 computational tools predict a weakening of the canonical 5' splice donor site, whereas the other 2/4 predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 250844 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.470C>T has been reported in the literature in an individual with clinical suspicion of a lysosomal storage disorder (Fernandez-Marmiesse_2014); however, this report does not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24767253). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Unidad de Diagnostico y Tratamiento de Errores Congenitos del Metabolismo. |
RCV000087098 | SCV000119955 | pathogenic | Neuronal ceroid lipofuscinosis 10 | no assertion criteria provided | research |