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

gnomAD frequency: 0.00001  dbSNP: rs758902805

Total submissions: 8

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.
Eurofins Ntd Llc (ga)	RCV000255516	SCV000339052	likely pathogenic	not provided	2016-01-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169061	SCV001231986	pathogenic	Niemann-Pick disease, type C1	2024-02-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 1205 of the NPC1 protein (p.Thr1205Lys). This variant is present in population databases (rs758902805, gnomAD 0.0009%). This missense change has been observed in individual(s) with Niemann-Pick Type C (PMID: 12955717, 22676771, 23430855, 27581084). ClinVar contains an entry for this variant (Variation ID: 188747). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects NPC1 function (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.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814078	SCV001755523	pathogenic	Abnormality of metabolism/homeostasis	2021-07-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804899	SCV002051426	pathogenic	Niemann-Pick disease, type C	2021-12-30	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.3614C>A (p.Thr1205Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251456 control chromosomes (gnomAD). c.3614C>A has been reported in the literature in multiple compound heterozygous individuals affected with Niemann-Pick Disease Type C (examples: Fancello_2009, Hron_2012, Di Rocco_2012 and Jahnova_2014). These data indicate that the variant is associated with disease. One publication reports experimental evidence evaluating a reduction in protein expression using compound heterozygous individul's fibroblast cells (Zampieri_2013). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000255516	SCV001959726	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255516	SCV001964815	pathogenic	not provided		no assertion criteria provided	clinical testing