ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3107C>T (p.Thr1036Met) (rs28942104)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000003092 SCV000220520 likely pathogenic Niemann-Pick disease type C1 2014-07-18 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000176149 SCV000227758 uncertain significance not provided 2014-08-14 criteria provided, single submitter clinical testing
Invitae RCV000003092 SCV000650844 pathogenic Niemann-Pick disease type C1 2017-06-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1036 of the NPC1 protein (p.Thr1036Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs28942104, ExAC 0.006%). This variant has been reported as homozygous or in combination with other NPC1 variants in multiple individuals affected with Niemann-Pick Type C disease (PMID: 26666848, 28222799, 9211849, 17160617, 12955717). This variant has also been observed on the opposite chromosome (in trans) from another pathogenic variant in an individual affected with Niemann-Pick type C (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 2958). Experimental studies of cells from NPC patients harboring this variant in combination with other NPC1 variants, including one of the prevalent NPC1 pathogenic variants p.Pro1007Ala, have shown abnormal accumulation of aneuploid cells, an effect simulating intracellular cholesterol accumulation (PMID: 23593294). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000781670 SCV000919893 pathogenic Niemann-Pick disease, type C 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The NPC1 c.3107C>T (p.Thr1036Met) variant involves the alteration of a highly conserved nucleotide. 4/4 in silico tools used predict a damaging outcome for this variant. This variant was found in 8/277208 control chromosomes at a frequency of 0.000029, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0028). The variant was identified in multiple affected individuals homozygously or in compound heterozygosity with clinically and biochemically confirmed Niemann-Pick C1 disease and is classified as Pathogenic by multiple clinical diagnostic laboratories/reputable databases. Taken together, this variant is classified as Pathogenic.
OMIM RCV000003092 SCV000023250 pathogenic Niemann-Pick disease type C1 1997-07-11 no assertion criteria provided literature only

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