Submissions for variant NM_000271.5(NPC1):c.3742_3745del (p.Leu1248fs)

dbSNP: rs774943545

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000576310	SCV000678022	likely pathogenic	Niemann-Pick disease, type C1	2014-01-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589877	SCV000696421	pathogenic	Niemann-Pick disease, type C	2017-07-03	criteria provided, single submitter	clinical testing	Variant summary: The NPC1 c.3742_3745delCTCA (p.Leu1248Valfs) variant (also known as 3741_3744delACTC) results in a premature termination codon, predicted to cause a truncated or absent NPC1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/121194 control chromosomes from ExAC at a frequency of 0.0000413, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0027735). The variant was detected in at least three patients with NPC. Variant downsteam of this variant c.3744_3747 delCAGT has also been reported in affected individual and listed as "DM-disease mutation" in HGMD, suggesitng this location is a mutation hotspot. Taken together, this variant is classified as pathogenic.
Invitae	RCV000576310	SCV001213659	pathogenic	Niemann-Pick disease, type C1	2023-10-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1248Valfs*3) in the NPC1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the NPC1 protein. This variant is present in population databases (rs774943545, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with Niemann-Pick type C (PMID: 10521290, 19744920). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3741_3744delACTC. ClinVar contains an entry for this variant (Variation ID: 487441). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001555014	SCV001776360	likely pathogenic	not provided	2019-09-19	criteria provided, single submitter	clinical testing	Reported in a family with a patient with Niemann-Pick type II disease; however, additional clinical information and biochemical studies on the patient were not provided (Greer et al., 1999); Reported in two patients with Niemann-Pick type C1 disease who have second NPC1 variants; however, segregation information was not provided to establish phase of the variants; for one patient, variant was reported as c.3741_3744delACTC due to the use of alternative nomenclature (Garver et al., 2010); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 31 amino acids are lost and replaced with 2 incorrect amino acids; This variant is associated with the following publications: (PMID: 28193631, 19744920, 10521290, 28082351)
Fulgent Genetics, Fulgent Genetics	RCV000576310	SCV002811009	likely pathogenic	Niemann-Pick disease, type C1	2022-05-14	criteria provided, single submitter	clinical testing