ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.1610T>C (p.Phe537Ser) (rs747310316)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group,Broad Institute RCV001004882 SCV001164366 uncertain significance Niemann-Pick disease type C1 2018-12-03 criteria provided, single submitter research The heterozygous p.Phe537Ser variant in NPC1 was identified by our study in the compound heterozygous state, with a VUS, in one individual with Niemann-Pick disease. The p.Phe537Ser variant in NPC1 has not been previously reported in individuals with Niemann-Pick disease but has been identified in 0.003249% (1/30778) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs747310316). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This missense variant affects the same residue as a variant reported in association with one individual with Niemann-Pick disease in the literature, p.Phe537Leu, slightly supporting that a change at this residue may not be tolerated (PMID: 16126423). In summary, the clinical significance of the p.Phe537Ser variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM5_Supporting (Richards 2015).

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