Submissions for variant NM_000271.5(NPC1):c.3410dup (p.Asn1137fs)

dbSNP: rs768299417

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825536	SCV000966852	likely pathogenic	Niemann-Pick disease, type C	2017-06-28	criteria provided, single submitter	clinical testing	The p.Asn1137LysfsX121 (NM_000271.4 c.3410_3411insA) variant in NPC1 has not be en previously reported in the literature. This variant has been identified in 1/ 111564 of European chromosomes by the Genome Aggregation Database (gnomAD, http: //gnomAD.broadinstitute.org; dbSNP rs768299417). It is predicted to cause a fram eshift, which alters the protein?s amino acid sequence beginning at position 113 7 and leads to a premature termination codon 121 amino acids downstream. This al teration is then predicted to lead to a truncated or absent protein. Biallelic l oss of function of the NPC1 gene is associated with Niemann-Pick disease, type C 1. In summary, although additional studies are required to fully establish a nul l effect on the protein, the p.Asn1137LysfsX121 variant in the NPC1 gene is lik ely pathogenic for Niemann-Pick disease, type C1 in an autosomal recessive manne r based on its predicted impact on the protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825536	SCV002500196	likely pathogenic	Niemann-Pick disease, type C	2022-03-08	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.3410dupA (p.Asn1137LysfsX121) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory and also reported in association with Niemann-Pick Disease Type C in the HGMD database. The variant allele was found at a frequency of 4e-06 in 251156 control chromosomes. To our knowledge, no occurrence of c.3410dupA in individuals affected with Niemann-Pick Disease Type C and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003605695	SCV004551770	pathogenic	Niemann-Pick disease, type C1	2022-12-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NPC1 protein in which other variant(s) (p.Arg1173Lysfs*85) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 666978). This variant has not been reported in the literature in individuals affected with NPC1-related conditions. This variant is present in population databases (rs768299417, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Asn1137Lysfs*121) in the NPC1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 142 amino acid(s) of the NPC1 protein.