Submissions for variant NM_000271.5(NPC1):c.721C>T (p.Gln241Ter)

gnomAD frequency: 0.00001  dbSNP: rs1064795718

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478255	SCV000571787	likely pathogenic	not provided	2016-10-25	criteria provided, single submitter	clinical testing	The Q241X variant in the NPC1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q241X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret Q241X as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694249	SCV000822684	pathogenic	Niemann-Pick disease, type C1	2023-09-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 422340). This variant has not been reported in the literature in individuals affected with NPC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln241*) 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).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000694249	SCV002769467	pathogenic	Niemann-Pick disease, type C1	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with type C1 Niemann-Pick disease (MIM#257220) and type D Niemann-Pick disease (MIM#257220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Phenotypic variability has been observed amongst individuals carrying the same pathogenic variant (PMID: 32138288. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least ten NMD-predicted variants that have been classified as likely pathogenic or pathogenic (DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individual. This variant has been classified as likely pathogenic and pathogenic by two clinical diagnostic laboratories (ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign