Submissions for variant NM_000271.5(NPC1):c.2761C>T (p.Gln921Ter)

dbSNP: rs786204512

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169199	SCV000220448	likely pathogenic	Niemann-Pick disease, type C1	2014-06-24	criteria provided, single submitter	literature only
Baylor Genetics	RCV000169199	SCV001163437	pathogenic	Niemann-Pick disease, type C1		criteria provided, single submitter	clinical testing
Invitae	RCV000169199	SCV001583026	pathogenic	Niemann-Pick disease, type C1	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln921*) in the NPC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NPC1 are known to be pathogenic (PMID: 9211850). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease type C (PMID: 11349231). ClinVar contains an entry for this variant (Variation ID: 188849). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001567278	SCV001790930	pathogenic	not provided	2021-03-02	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19252935, 32138288, 11349231, 25525159)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271441	SCV002555914	pathogenic	Niemann-Pick disease, type C	2022-06-16	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.2761C>T (p.Gln921X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251470 control chromosomes (gnomAD). c.2761C>T has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (e.g. Sun_2001, Fancello_2009, Romanello_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000169199	SCV002791372	pathogenic	Niemann-Pick disease, type C1	2021-11-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398865	SCV004103677	pathogenic	NPC1-related condition	2023-08-16	criteria provided, single submitter	clinical testing	The NPC1 c.2761C>T variant is predicted to result in premature protein termination (p.Gln921*). This variant has been reported in the presumably homozygous and compound heterozygous states in multiple individuals with Niemann-Pick disease type C (Table 2, Sun et al. 2001. PubMed ID: 11349231; Table 1, Fancello et al. 2009. PubMed ID: 19252935; Table 1, Dardis et al. 2020. PubMed ID: 32138288). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in NPC1 are expected to be pathogenic. This variant is interpreted as pathogenic.