Submissions for variant NM_000271.5(NPC1):c.410C>T (p.Thr137Met)

gnomAD frequency: 0.00001  dbSNP: rs372947142

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522597	SCV000617719	uncertain significance	not provided	2017-07-10	criteria provided, single submitter	clinical testing	The T137M variant in the NPC1 gene has been reported previously in association with Niemann-Pick disease type C, when present in the homozygous state or when seen with another variant, however, some patients have been reported to have normal biochemical studies (Sun et al., 2001; Fernandez-Valero et al., 2005; Garver et al., 2010; Akizu et al., 2013). Additionally, functional studies showed T137M exhibits normal binding to both 25-hydroxycholesterol and cholesterol (Infante et al., 2008). The T137M 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). The T137M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Threonine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret T137M as a variant of uncertain significance.
Baylor Genetics	RCV000674009	SCV001163441	pathogenic	Niemann-Pick disease, type C1		criteria provided, single submitter	clinical testing
Invitae	RCV000674009	SCV001582238	pathogenic	Niemann-Pick disease, type C1	2024-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 137 of the NPC1 protein (p.Thr137Met). This variant is present in population databases (rs372947142, gnomAD 0.003%). This missense change has been observed in individual(s) with Niemann-Pick Type C (PMID: 11349231, 26666848, 27139891, 27378690). ClinVar contains an entry for this variant (Variation ID: 449504). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPC1 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NPC1 function (PMID: 17989072). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000674009	SCV002060170	likely pathogenic	Niemann-Pick disease, type C1	2021-11-03	criteria provided, single submitter	clinical testing	NM_000271.4(NPC1):c.410C>T(T137M) is a missense variant classified as likely pathogenic in the context of Niemann-Pick disease type C1. T137M has been observed in cases with relevant disease (PMID: 11349231, 23453666, 16098014, 19744920, 27139891, 26666848). Functional assessments of this variant are available in the literature (PMID: 17989072). T137M has been observed in population frequency databases (gnomAD: AMR 0.003%). In summary, NM_000271.4(NPC1):c.410C>T(T137M) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226316	SCV003922603	pathogenic	Niemann-Pick disease, type C	2023-03-18	criteria provided, single submitter	clinical testing	Variant summary: NPC1 c.410C>T (p.Thr137Met) results in a non-conservative amino acid change located in the Niemann-Pick C1, N-terminal domain (IPR032190) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251402 control chromosomes. c.410C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type C (example, PMID: 27378690, 29429782, 23453666). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported although one study reported normal binding to both 25-Hydroxycholesterol and Cholesterol (PMID: 17989072). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV000674009	SCV001459997	uncertain significance	Niemann-Pick disease, type C1	2020-09-16	no assertion criteria provided	clinical testing