Submissions for variant NM_000271.5(NPC1):c.3611_3614del (p.Leu1204fs)

dbSNP: rs786200879

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003113	SCV002235085	pathogenic	Niemann-Pick disease, type C1	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1204Glnfs*37) in the NPC1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acid(s) of the NPC1 protein. This variant is present in population databases (rs786200879, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with Niemann–Pick type C (PMID: 12554680). ClinVar contains an entry for this variant (Variation ID: 2979). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects NPC1 function (PMID: 12554680). This variant disrupts a region of the NPC1 protein in which other variant(s) (p.Leu1248Valfs*3) have been determined to be pathogenic (PMID: 10521290, 19744920). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387713	SCV004099548	pathogenic	Niemann-Pick disease, type C	2023-09-01	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.3611_3614delTTAC (p.Leu1204GlnfsX37) 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. The variant allele was found at a frequency of 1.2e-05 in 251450 control chromosomes (gnomAD). c.3611_3614delTTAC has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (Blom_2003, Park_2003, Reunert_2015). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant resulted in an unstable NPC1 protein and presumably does not contribute significantly to the NPC1 immunoreactivity of the patient cells (Blom_2003). The following publications have been ascertained in the context of this evaluation (PMID: 12554680, 12955717, 26981555, 26338816, 25764212). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398426	SCV004104577	likely pathogenic	NPC1-related disorder	2022-10-24	criteria provided, single submitter	clinical testing	The NPC1 c.3611_3614delTTAC variant is predicted to result in a frameshift and premature protein termination (p.Leu1204Glnfs*37). This variant, along with two other variants in NPC1, was reported in an individual with an infantile form of Niemann-Pick disease, type C (Blom et al. 2003. PubMed ID: 12554680). Additional functional analyses show that this variant impacts protein function (Blom et al. 2003. PubMed ID: 12554680). This variant is reported in 0.0092% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-21113458-TGTAA-T). Frameshift variants in NPC1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.
OMIM	RCV000003113	SCV000023271	pathogenic	Niemann-Pick disease, type C1	2003-02-01	no assertion criteria provided	literature only