Submissions for variant NM_001909.5(CTSD):c.8C>T (p.Pro3Leu)

gnomAD frequency: 0.00067  dbSNP: rs757712173

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000727458	SCV000240892	uncertain significance	not provided	2018-04-10	criteria provided, single submitter	clinical testing	The P3L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P3L variant is not observed at a significant frequency in large population cohorts; however, limited data are available (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P3L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000231366	SCV000287212	uncertain significance	Neuronal ceroid lipofuscinosis	2022-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3 of the CTSD protein (p.Pro3Leu). This variant is present in population databases (rs757712173, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CTSD-related conditions. ClinVar contains an entry for this variant (Variation ID: 205353). 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: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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.
Eurofins Ntd Llc (ga)	RCV000727458	SCV000708720	uncertain significance	not provided	2017-06-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763725	SCV000894609	uncertain significance	Neuronal ceroid lipofuscinosis 10	2021-09-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000763725	SCV001260437	uncertain significance	Neuronal ceroid lipofuscinosis 10	2018-01-13	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	RCV002372146	SCV002685049	uncertain significance	Inborn genetic diseases	2020-07-22	criteria provided, single submitter	clinical testing	The p.P3L variant (also known as c.8C>T), located in coding exon 1 of the CTSD gene, results from a C to T substitution at nucleotide position 8. The proline at codon 3 is replaced by leucine, 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.
PreventionGenetics, part of Exact Sciences	RCV003967472	SCV004779924	likely benign	CTSD-related condition	2020-08-05	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000727458	SCV001806948	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000727458	SCV001966570	likely benign	not provided		no assertion criteria provided	clinical testing