ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3614C>A (p.Thr1205Lys) (rs758902805)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169061 SCV000220224 likely pathogenic Niemann-Pick disease type C1 2014-04-07 criteria provided, single submitter literature only
GeneDx RCV000255516 SCV000322456 pathogenic not provided 2016-02-21 criteria provided, single submitter clinical testing The T1205K pathogenic variant in the NPC1 gene has been reported previously has been reported previously in association with autosomal recessive Niemann-Pick disease, type C when in trans with another disease-causing NPC1 variant (Zampieri et al., 2012; Park et al., 2003). Additionally, studies in fibroblast cell lines from patients with the T1205K variant show that this variant is associated with very low cholesterol esterification, resulting in an impact on protein function, folding, trafficking, and degradation (Zampieri et al., 2012; Park et al., 2003). The T1205K 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. The T1205K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T1205K as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255516 SCV000339052 likely pathogenic not provided 2016-01-29 criteria provided, single submitter clinical testing
Invitae RCV000169061 SCV001231986 pathogenic Niemann-Pick disease type C1 2019-12-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 1205 of the NPC1 protein (p.Thr1205Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is present in population databases (rs758902805, ExAC 0.002%). This variant has been observed to be homozygous or in combination with another NPC1 variant in several individuals affected with Niemann-Pick Type C (PMID: 12955717, 22676771, 23430855, 27581084). ClinVar contains an entry for this variant (Variation ID: 188747). This variant has been reported to affect NPC1 protein function in yeast system (PMID: 16138904). This variant disrupts the p.Thr1205 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11182931, 22676771, 25236789). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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