Submissions for variant NM_000271.5(NPC1):c.1020_1021del (p.Arg341fs)

dbSNP: rs1555637255

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520330	SCV000620579	likely pathogenic	not provided	2017-08-29	criteria provided, single submitter	clinical testing	The c.1020_1021delAC variant in the NPC1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1020_1021delAC variant causes a frameshift starting with codon Arginine 341, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 38 of the new reading frame, denoted p.Arg341LeufsX38. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1020_1021delAC variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1020_1021delAC as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002528256	SCV003333393	pathogenic	Niemann-Pick disease, type C1	2022-03-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Arg341Leufs*38) 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 variant has not been reported in the literature in individuals affected with NPC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 451826).