Submissions for variant NM_000271.5(NPC1):c.810CAT[1] (p.Ile271del)

dbSNP: rs1243863645

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521088	SCV000617718	likely pathogenic	not provided	2017-04-27	criteria provided, single submitter	clinical testing	The c.813_815delCAT variant in the NPC1 gene has been reported in an individual with Neiman-Pick C disease with impaired cholesterol esterification rate who also possessed a second variant in the NPC1 gene (Sun et al.,2001). The c.813_815delCAT variant causes an in-frame deletion of one amino acid, Isoleucine 271, denotedp.Ile271del. This amino acid deletion occurs at a position that is conserved across species. The c.813_815delCATvariant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; ExomeVariant Server).We interpret c.813_815delCAT as a likely pathogenic variant.
Invitae	RCV000670904	SCV001213593	uncertain significance	Niemann-Pick disease, type C1	2022-05-25	criteria provided, single submitter	clinical testing	This variant, c.813_815del, results in the deletion of 1 amino acid(s) of the NPC1 protein (p.Ile271del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Niemann-Pick disease type C (PMID: 11349231, 31130284). ClinVar contains an entry for this variant (Variation ID: 449503). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV000521088	SCV002501635	likely pathogenic	not provided	2021-12-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282197	SCV002572480	likely pathogenic	Niemann-Pick disease, type C	2022-08-04	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.813_815delCAT (p.Ile271del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 250742 control chromosomes. c.813_815delCAT has been reported in the literature in individuals affected with features of Niemann-Pick Disease Type C and in settings of clinical exome sequencing in an affected consanguineous population (example, Sun_2001, Monies_2019). 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (LP, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl	RCV000670904	SCV000795818	uncertain significance	Niemann-Pick disease, type C1	2017-11-17	no assertion criteria provided	clinical testing