ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3570_3573dup (p.Ala1192fs) (rs750323164)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000485447 SCV000331280 pathogenic not provided 2016-08-25 criteria provided, single submitter clinical testing
GeneDx RCV000485447 SCV000567049 likely pathogenic not provided 2017-03-10 criteria provided, single submitter clinical testing The c.3570_3573dupACTT variant has been previously reported in an individual with Niemann-Pick disease, type Cusing the alternate nomenclature c.3573_3574insACTT. This individual was reported to harbor another variant in theNPC1 gene (Park et al., 2003). The c.3570_3573dupACTT variant causes a frameshift starting with codon Alanine1192, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 67 of the newreading frame, denoted p.Ala1192ThrfsX67. This variant is predicted to cause loss of normal protein function throughprotein truncation as the last 87 amino acids of the protein are replaced with 66 incorrect ones. Thec.3570_3573dupACTT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016;1000 Genomes Consortium et al., 2015; Exome Variant Server). In summary, we interpret c.3570_3573dupACTT aslikely pathogenic.
Invitae RCV001061435 SCV001226179 pathogenic Niemann-Pick disease type C1 2019-02-19 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the NPC1 gene (p.Ala1192Thrfs*67). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 87 amino acids of the NPC1 protein. This variant is present in population databases (rs750323164, ExAC 0.002%). This variant has been observed in an individual affected with Niemann-Pick disease type C (PMID: 12955717). This variant is also known as c.3573_3574insACTT in the literature. ClinVar contains an entry for this variant (Variation ID: 419323). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant disrupts the C-terminus of the NPC1 protein. Other variant(s) that disrupt this region (p.Leu1248Valfs*3, p.Phe1221Serfs*21, p.Pro1245Argfs*12, p.Pro1245Cysfs*12) have been observed in individuals with NPC1-related conditions (PMID: 10521290, 11479732, 12401890, 25425405). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.

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