Submissions for variant NM_000391.4(TPP1):c.947C>A (p.Ala316Asp)

gnomAD frequency: 0.00007  dbSNP: rs149463616

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489363	SCV000576818	uncertain significance	not provided	2022-02-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000489363	SCV000753889	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 316 of the TPP1 protein (p.Ala316Asp). This variant is present in population databases (rs149463616, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TPP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 426392). 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 not expected to disrupt TPP1 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.
Ambry Genetics	RCV002311808	SCV000847244	uncertain significance	Inborn genetic diseases	2016-07-21	criteria provided, single submitter	clinical testing	The p.A316D variant (also known as c.947C>A), located in coding exon 8 of the TPP1 gene, results from a C to A substitution at nucleotide position 947. The alanine at codon 316 is replaced by aspartic acid, an amino acid with dissimilar properties. This variant was previously reported in the SNPDatabase as rs149463616, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Illumina Laboratory Services, Illumina	RCV001102830	SCV001259522	uncertain significance	Neuronal ceroid lipofuscinosis 2	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000489363	SCV001716085	uncertain significance	not provided	2019-07-29	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001102830	SCV001458787	uncertain significance	Neuronal ceroid lipofuscinosis 2	2020-01-24	no assertion criteria provided	clinical testing