ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1241A>T (p.Asn414Ile)

gnomAD frequency: 0.00051  dbSNP: rs146798796
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000724076 SCV000224823 uncertain significance not provided 2014-10-13 criteria provided, single submitter clinical testing
GeneDx RCV000724076 SCV000243434 uncertain significance not provided 2023-05-01 criteria provided, single submitter clinical testing Reported previously in the heterozygous state in a patient with a definite or probable diagnosis of ALS who also harbored a splice variant in the TPP1 gene (Garton et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30676690, 28717666, 27776828, 36031433)
Illumina Laboratory Services, Illumina RCV000322901 SCV000373322 uncertain significance Neuronal ceroid lipofuscinosis 2 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.
Invitae RCV000724076 SCV000548742 uncertain significance not provided 2022-10-17 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 414 of the TPP1 protein (p.Asn414Ile). This variant is present in population databases (rs146798796, gnomAD 0.05%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 28717666). ClinVar contains an entry for this variant (Variation ID: 193583). 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 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 RCV002316995 SCV000850569 uncertain significance Inborn genetic diseases 2017-12-18 criteria provided, single submitter clinical testing The p.N414I variant (also known as c.1241A>T), located in coding exon 10 of the TPP1 gene, results from an A to T substitution at nucleotide position 1241. The asparagine at codon 414 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Athena Diagnostics Inc RCV000724076 SCV001146219 uncertain significance not provided 2019-07-15 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001280959 SCV001468331 uncertain significance Neuronal ceroid lipofuscinosis 2; Autosomal recessive spinocerebellar ataxia 7 2021-03-30 criteria provided, single submitter clinical testing TPP1 NM_000391.3 exon 10 p.Asn414Ile (c.1241A>T): This variant has not been reported in the literature but is present in 0.05% (70/129174) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-6636698-T-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:193583). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Natera, Inc. RCV000322901 SCV001455829 uncertain significance Neuronal ceroid lipofuscinosis 2 2020-09-16 no assertion criteria provided clinical testing

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