ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.827A>T (p.Asp276Val) (rs763162812)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189773 SCV000243421 pathogenic not provided 2014-04-21 criteria provided, single submitter clinical testing p.Asp276Val (GAT>GTT): c.827 A>T in exon 7 of the TPP1 gene (NM_000391.3)The D276V missense mutation has been previously reported in three individuals with a clinical phenotype of late-infantile neuronal ceroid lipofuscinosis (Kohan et al., 2009). In two of the affected individuals, D276V was detected as a homozygous mutation and in the third individual, as a compound heterozygous mutation with a second disease-causing frameshift mutation. Parental studies were performed for all three cases and each parent was confirmed to be heterozygous for only one mutation. D276V is a non-conservative amino acid substitution, as a a negatively charged, polar Aspartic acid residue is replaced by an uncharged, non-polar Valine residue. D276V alters a highly conserved position in the TPP1 protein and functional studies indicate that this mutation reduces catalytic activity of TPP1 (Walus et al., 2005). The variant is found in EPILEPSY,CHILD-EPI panel(s).
Counsyl RCV000666770 SCV000791120 pathogenic Ceroid lipofuscinosis neuronal 2 2017-05-02 criteria provided, single submitter clinical testing
Invitae RCV000811297 SCV000951555 pathogenic Neuronal ceroid lipofuscinosis 2019-06-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 276 of the TPP1 protein (p.Asp276Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs763162812, ExAC 0.02%). This variant has been observed in several individuals affected with neuronal ceroid lipofuscinosis type 2 (PMID: 19793312, 25976102, 23266810, 22832778). ClinVar contains an entry for this variant (Variation ID: 207581). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan RCV000666770 SCV001146849 pathogenic Ceroid lipofuscinosis neuronal 2 2020-01-20 criteria provided, single submitter clinical testing

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