ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3182T>C (p.Ile1061Thr) (rs80358259)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254672 SCV000208911 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing The I1061T variant in the NPC1 gene is a common variant observed in individuals with Niemann-Pick disease, type C and represents 15-20% of all disease alleles (Millat et al., 1999; Pipalia et al., 2011). In vitro studies of the I1061T variant in human fibroblasts demonstrated that, although the protein is synthesized normally, it fails to undergo normal post-translational glycosylation, which leads to a misfolded protein and proteasomal degradation in the endoplasmic reticulum (Gelsthorpe et al., 2008). The I1061T 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. We interpret I1061T as a pathogenic variant.
Courtagen Diagnostics Laboratory,Courtagen Life Sciences RCV000003101 SCV000236543 pathogenic Niemann-Pick disease type C1 2015-03-10 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000254672 SCV000330979 pathogenic not provided 2017-05-05 criteria provided, single submitter clinical testing
Counsyl RCV000003101 SCV000485238 pathogenic Niemann-Pick disease type C1 2016-03-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000003101 SCV000596044 pathogenic Niemann-Pick disease type C1 2016-11-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000003101 SCV000611222 pathogenic Niemann-Pick disease type C1 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587869 SCV000696420 pathogenic Niemann-Pick disease, type C 2016-09-02 criteria provided, single submitter clinical testing Variant summary: The NPC1 c.3182T>C (p.Ile1061Thr) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPs&GO and MutationTaster not captured due to low reliability index). This variant was found in 29/121142 control chromosomes at a frequency of 0.0002394, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0027735). This variant has been shown to be the most common mutation in NPC patients (Millat_1999). Functional study showed that the protein levels of NPC1 I1061T was significantly lower than the wild-type NPC1 due to misfolding (Gelsthorpe_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000624446 SCV000742470 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Invitae RCV000003101 SCV000836750 pathogenic Niemann-Pick disease type C1 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1061 of the NPC1 protein (p.Ile1061Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs80358259, ExAC 0.04%). This variant is clearly defined as a Niemann-Pick disease type C causative allele and accounts for 15-20% of disease alleles in the United States and Western Europe (PMID: 10521297, 16126423, 25149939, 20521171). ClinVar contains an entry for this variant (Variation ID: 2967). Experimental studies have shown that this missense change impairs proper protein localization and leads to proteasomal degradation in cell culture (PMID: 18216017, 25637190). Studies in mice have shown that this variant recapitulates disease in vivo (PMID: 26019327). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003101 SCV000023259 pathogenic Niemann-Pick disease type C1 2008-03-28 no assertion criteria provided literature only
GeneReviews RCV000003101 SCV000040577 pathologic Niemann-Pick disease type C1 2008-07-22 no assertion criteria provided curation Converted during submission to Pathogenic.
Division of Human Genetics,Children's Hospital of Philadelphia RCV000003101 SCV000238437 pathogenic Niemann-Pick disease type C1 2015-05-07 no assertion criteria provided research The heterozygous variant in the NPC1 gene (c.3182T>C; p.Ile1061Thr) is considered pathogenic. This variant was seen in 29 alleles out of 120942 total interrogated at this position in the ExAC database. This variant has been previously published in multiple individuals (Fernandez-Valero et al. 2005; PMID: 16098014; MIlat et al. 1999 PMID: 10521297; Yamamoto et al. 1999, PMID: 10480349) and functional studies performed show that the resulting protein fails to localize properly (Gelsthorpe et al 2008, PMID: 18216017).

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