ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1312C>T (p.Gln438Ter) (rs750292546)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825537 SCV000966853 likely pathogenic Niemann-Pick disease, type C 2019-02-11 criteria provided, single submitter clinical testing The p.Gln438X variant in NPC1 has not been previously reported in individuals with Niemann-Pick disease type C, but has been identified in 0.003% (1/34590) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 438, which is predicted to lead to a truncated or absent protein. Loss of function of the NPC1 gene is an established disease mechanism in Niemann-Pick disease type C. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Niemann-Pick disease type C. ACMG/AMP Criteria applied: PVS1, PM2.

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