ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3794A>T (p.Glu1265Val)

gnomAD frequency: 0.00002  dbSNP: rs751251790
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000281509 SCV000345904 uncertain significance not provided 2018-07-25 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002522045 SCV003448440 uncertain significance Niemann-Pick disease, type C1 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1265 of the NPC1 protein (p.Glu1265Val). This variant is present in population databases (rs751251790, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NPC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 291193). 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 NPC1 protein function with a negative predictive value of 95%. 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 RCV003343748 SCV004057734 uncertain significance Inborn genetic diseases 2023-07-30 criteria provided, single submitter clinical testing The c.3794A>T (p.E1265V) alteration is located in exon 25 (coding exon 25) of the NPC1 gene. This alteration results from a A to T substitution at nucleotide position 3794, causing the glutamic acid (E) at amino acid position 1265 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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