Submissions for variant NM_000271.5(NPC1):c.3570_3573dup (p.Ala1192fs)

gnomAD frequency: 0.00001  dbSNP: rs750323164

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000485447	SCV000331280	pathogenic	not provided	2016-08-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000485447	SCV000567049	likely pathogenic	not provided	2017-03-10	criteria provided, single submitter	clinical testing	The c.3570_3573dupACTT variant has been previously reported in an individual with Niemann-Pick disease, type Cusing the alternate nomenclature c.3573_3574insACTT. This individual was reported to harbor another variant in theNPC1 gene (Park et al., 2003). The c.3570_3573dupACTT variant causes a frameshift starting with codon Alanine1192, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 67 of the newreading frame, denoted p.Ala1192ThrfsX67. This variant is predicted to cause loss of normal protein function throughprotein truncation as the last 87 amino acids of the protein are replaced with 66 incorrect ones. Thec.3570_3573dupACTT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016;1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we interpret c.3570_3573dupACTT aslikely pathogenic.
Invitae	RCV001061435	SCV001226179	pathogenic	Niemann-Pick disease, type C1	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala1192Thrfs*67) in the NPC1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 87 amino acid(s) of the NPC1 protein. This variant is present in population databases (rs750323164, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease type C (PMID: 12955717). This variant is also known as c.3573_3574insACTT. ClinVar contains an entry for this variant (Variation ID: 419323). 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.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001061435	SCV002061670	pathogenic	Niemann-Pick disease, type C1	2021-10-29	criteria provided, single submitter	clinical testing	PVS1, PM2, PS3_Moderate
Genetic Services Laboratory, University of Chicago	RCV000485447	SCV002064481	pathogenic	not provided	2017-09-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003486851	SCV004241437	likely pathogenic	Niemann-Pick disease, type C	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.3570_3573dupACTT (p.Ala1192ThrfsX67) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. The variant allele was found at a frequency of 1.2e-05 in 250774 control chromosomes (gnomAD). c.3570_3573dupACTT (also known as c.3573_3574insACTT) has been reported in the literature in individuals affected with Niemann-Pick Disease Type C (example: Saito_2002, Park_2003, Garver_2010). Similar truncations have been reported in bi-allelic patients affected with Niemann-Pick Disease Type C (PMID: 9211849, 16126423). The following publications have been ascertained in the context of this evaluation (PMID: 19744920, 12955717, 12205649). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.