ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3425T>C (p.Met1142Thr) (rs778878523)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414430 SCV000490671 likely pathogenic not provided 2016-10-05 criteria provided, single submitter clinical testing The M1142T variant in the NPC1 gene has been reported previously in association with Niemann-Pick disease type C (NPC) in multiple unrelated individuals when present with a second variant in the NPC1 gene (Millat et al., 2001; Sun et al., 2001; Fancello et al., 2009; Macias-Vidal et al., 2011). The M1142T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M1142T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (N1137I, G1140V, V1141G, W1145R) have been reported in the Human Gene Mutation Database in association with NPC (Stenson et al., 2014), supporting the functional importance of this region of the protein. The M1142T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Counsyl RCV000665209 SCV000789285 likely pathogenic Niemann-Pick disease type C1 2017-01-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000665209 SCV000893485 likely pathogenic Niemann-Pick disease type C1 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000665209 SCV000938960 likely pathogenic Niemann-Pick disease type C1 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1142 of the NPC1 protein (p.Met1142Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs778878523, ExAC 0.002%). This variant has been observed in several individuals affected with Niemann–Pick type C (PMID: 11349231, 20718790, 11333381, 25239094). ClinVar contains an entry for this variant (Variation ID: 372435). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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