Submissions for variant NM_001909.5(CTSD):c.1162G>A (p.Val388Ile)

gnomAD frequency: 0.00013  dbSNP: rs202073338

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726035	SCV000341368	uncertain significance	not provided	2016-06-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000395099	SCV000369551	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.
GeneDx	RCV000726035	SCV000566653	uncertain significance	not provided	2018-10-24	criteria provided, single submitter	clinical testing	The V388I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V388I variant is observed in 16/34412 (0.05%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The V388I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000808865	SCV000948992	uncertain significance	Neuronal ceroid lipofuscinosis	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 388 of the CTSD protein (p.Val388Ile). This variant is present in population databases (rs202073338, gnomAD 0.05%). 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: 287566). 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: "Possibly Damaging"; 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.
Ambry Genetics	RCV002356389	SCV002623435	uncertain significance	Inborn genetic diseases	2017-09-20	criteria provided, single submitter	clinical testing	The p.V388I variant (also known as c.1162G>A), located in coding exon 9 of the CTSD gene, results from a G to A substitution at nucleotide position 1162. The valine at codon 388 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly 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.
Fulgent Genetics, Fulgent Genetics	RCV000395099	SCV002782196	uncertain significance	Neuronal ceroid lipofuscinosis 10	2021-12-10	criteria provided, single submitter	clinical testing