Submissions for variant NM_000271.5(NPC1):c.3019C>G (p.Pro1007Ala)

gnomAD frequency: 0.00021  dbSNP: rs80358257

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254671	SCV000208910	pathogenic	not provided	2021-11-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24676439, 28332184, 32222928, 31980526, 23487299, 24570279, 25131710, 23183285, 28105569, 26981555, 23427322, 26790753, 10521290, 26338816, 24119781, 25236789, 30202070, 28186668, 24915861, 23773996, 23791518, 24386122, 14639697, 11349231, 26666848, 30548255, 16126423, 32138288, 32488064, 33726816)
Eurofins Ntd Llc (ga)	RCV000254671	SCV000227615	pathogenic	not provided	2014-12-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000003100	SCV000407850	pathogenic	Niemann-Pick disease, type C1	2017-04-27	criteria provided, single submitter	clinical testing	The NPC1 gene is one of two genes in which variants are known to cause Niemann-Pick disease type C. The NPC1 c.3019C>G (p.Pro1007Ala) variant is widely reported as a pathogenic variant and is the second most common pathogenic allele in Western Europe and the US (Patterson et al. 2000). Across a selection of the available literature, the p.Pro1007Ala variant has been identified in at least 44 Niemann-Pick disease type C patients including eight in a homozygous state, 33 in a compound heterozygous state, and three in a heterozygous state (Greer et al. 1999; Ribeiro et al. 2001; Sun et al. 2001; Millat et al. 2001; Bauer et al. 2002; Tarugi et al. 2002; Fernandez-Valero et al. 2005; Jahnova et al. 2014; Pina-Aguilar et al. 2014; Abela et al. 2014; Imrie et al. 2015). The p.Pro1007Ala variant is described as being associated with a variant form of Niemann-Pick disease type C, which presents with a non-classical biochemical profile (Millat et al. 2001; Sun et al. 2001). Control data are unavailable for this variant, which is reported at a frequency of 0.00019 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence the p.Pro1007Ala variant is classified as pathogenic for Niemann-Pick disease type C. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415371	SCV000492760	pathogenic	Cataplexy; Cerebellar ataxia; Cognitive impairment; Headache; Speech apraxia; Postural instability	2014-10-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000003100	SCV000611221	pathogenic	Niemann-Pick disease, type C1	2017-05-18	criteria provided, single submitter	clinical testing
Invitae	RCV000003100	SCV000650843	pathogenic	Niemann-Pick disease, type C1	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1007 of the NPC1 protein (p.Pro1007Ala). This variant is present in population databases (rs80358257, gnomAD 0.02%). This missense change has been observed in individual(s) with Niemann-Pick type C disease (PMID: 10521290, 11754101, 14639697, 23183285, 23791518, 25425405, 26981555). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2966). 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 does not substantially affect NPC1 function (PMID: 15937921). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000321958	SCV000696419	pathogenic	Niemann-Pick disease, type C	2017-04-26	criteria provided, single submitter	clinical testing	Variant summary: The NPC1 c.3019C>G (p.Pro1007Ala) variant involves the alteration of a highly conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 14/121408 control chromosomes at a frequency of 0.0001153, which does not exceed the estimated maximal expected allele frequency of a pathogenic NPC1 variant (0.0027735). The variant has been reported numerous times in the literature in affected individuals in both the homozygous and compound heterozygous state. Multiple clinical labs classify the variant as pathogenic. Taken together, this variant is classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000003100	SCV000744742	uncertain significance	Niemann-Pick disease, type C1	2017-08-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000003100	SCV001140857	pathogenic	Niemann-Pick disease, type C1	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000003100	SCV001193996	pathogenic	Niemann-Pick disease, type C1	2019-12-24	criteria provided, single submitter	clinical testing	NM_000271.4(NPC1):c.3019C>G(P1007A) is classified as pathogenic in the context of Niemann-Pick disease type C1. Sources cited for classification include the following: PMID 16098014, 11479732 and 11333381. Classification of NM_000271.4(NPC1):c.3019C>G(P1007A) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.‚Äã
CeGaT Center for Human Genetics Tuebingen	RCV000254671	SCV001249523	pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000254671	SCV001447180	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000003100	SCV001528308	pathogenic	Niemann-Pick disease, type C1	2018-10-28	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing for Niemann-Pick disease, type C [PMID 14639697, 23773996, 23791518, 23427322, 26666848]
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000003100	SCV001554476	pathogenic	Niemann-Pick disease, type C1	2021-04-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000003100	SCV002018351	pathogenic	Niemann-Pick disease, type C1	2020-02-27	criteria provided, single submitter	clinical testing
DASA	RCV000003100	SCV002107103	pathogenic	Niemann-Pick disease, type C1	2022-03-05	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 12955717; 20554533) - PS3_moderate.The c.3019C>G;p.(Pro1007Ala) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 2966; PMID 14639697; PMID: 23773996; PMID: 23791518; PMID: 23427322; PMID: 26666848) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain PM1. The variant is present at low allele frequencies population databases (rs80358257 – gnomAD 0.001167%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Pro1007Ala) was detected in trans with a pathogenic variant (PMID 14639697; PMID: 23773996; PMID: 23791518) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Ambry Genetics	RCV002512691	SCV003556234	pathogenic	Inborn genetic diseases	2021-01-12	criteria provided, single submitter	clinical testing	The c.3019C>G (p.P1007A) alteration is located in exon 20 (coding exon 20) of the NPC1 gene. This alteration results from a C to G substitution at nucleotide position 3019, causing the proline (P) at amino acid position 1007 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD) database, the NPC1 c.3019C>G alteration was observed in 0.01% (33/282878) of total alleles studied, with a frequency of 0.02% (29/129196) in the European (non-Finnish) subpopulation. This mutation has been identified in numerous homozygous and compound heterozygous individuals with NPC1-related Niemann-Pick disease, many with intermediate or "variant" levels of cholesterol esterification (Millat, 2001; Jahnova, 2014; Reunert, 2016; Musalkova, 2020; Dardis, 2020). The p.P1007A alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000003100	SCV003807753	pathogenic	Niemann-Pick disease, type C1	2022-09-09	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM2 supporting, PM3 very strong, PP1 supporting, PP3 supporting
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003100	SCV004027757	pathogenic	Niemann-Pick disease, type C1	2023-07-24	criteria provided, single submitter	clinical testing	Identified as compund heterozygous with NM_000271.5:c.1997G>A. Criteria applied: PM3_VSTR,PM5,PM2_SUP,PP3
PreventionGenetics, part of Exact Sciences	RCV003952339	SCV004771468	pathogenic	NPC1-related disorder	2023-11-21	criteria provided, single submitter	clinical testing	The NPC1 c.3019C>G variant is predicted to result in the amino acid substitution p.Pro1007Ala. This variant has been well-documented as causative for Niemann-Pick disease (see for example Greer et al 1999. PubMed ID: 10521290; Bauer et al. 2013. PubMed ID: 23773996; Mavridou et al. 2017. PubMed ID: 28105569; Dardis et al. 2020. PubMed ID: 32138288). Other missense variants, affecting the same amino acid (p.Pro1007Leu, p.Pro1007Arg), have also been reported to be causative for Niemann-Pick disease (Imrie et al. 2015. PubMed ID: 26666848; http://www.hgmd.cf.ac.uk/). This variant is reported in 0.022% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
OMIM	RCV000003100	SCV000023258	pathogenic	Niemann-Pick disease, type C1	2001-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000003100	SCV000040575	not provided	Niemann-Pick disease, type C1		no assertion provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000003100	SCV000733755	pathogenic	Niemann-Pick disease, type C1		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000003100	SCV000745697	likely pathogenic	Niemann-Pick disease, type C1	2016-11-03	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000003100	SCV001453835	pathogenic	Niemann-Pick disease, type C1	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000254671	SCV001952294	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000254671	SCV001970102	likely pathogenic	not provided		no assertion criteria provided	clinical testing