ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3056A>G (p.Tyr1019Cys)

gnomAD frequency: 0.00001  dbSNP: rs781261962
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412438 SCV000486996 likely pathogenic Niemann-Pick disease, type C1 2016-09-22 criteria provided, single submitter clinical testing
Invitae RCV000412438 SCV002227787 pathogenic Niemann-Pick disease, type C1 2023-07-14 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1019 of the NPC1 protein (p.Tyr1019Cys). This variant is present in population databases (rs781261962, gnomAD 0.002%). This missense change has been observed in individual(s) with Niemann-Pick type C (PMID: 32138288). ClinVar contains an entry for this variant (Variation ID: 371419). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function. Studies have shown that this missense change alters NPC1 gene expression (PMID: 23430855). For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000412438 SCV002574927 pathogenic Niemann-Pick disease, type C1 2022-04-12 criteria provided, single submitter clinical testing A Homozygous missense variation in exon 21 of the NPC1 gene that results in the amino acid substitution of Cystine for Tyrosine at codon 1019 was detected. The observed variant c.3056A>G (p.Tyr1019Cys) has not been reported in the 1000 genomes and has a MAF of 000796% in the gnomAD database. The in silico prediction of the variant is damaging by PolyPhen-2 (HumDiv), LRT and MutationTaster2. In summary, the variant meets our criteria to be classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000412438 SCV002778115 likely pathogenic Niemann-Pick disease, type C1 2022-02-15 criteria provided, single submitter clinical testing

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