rs80358257
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_000271.5(NPC1):c.3019C>G(p.Pro1007Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1007L) has been classified as Pathogenic.
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.3019C>G | p.Pro1007Ala | missense_variant | 20/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.3019C>G | p.Pro1007Ala | missense_variant | 20/25 | 1 | NM_000271.5 | P1 | |
NPC1 | ENST00000591051.1 | c.2098C>G | p.Pro700Ala | missense_variant | 13/18 | 2 | |||
NPC1 | ENST00000591075.1 | n.652C>G | non_coding_transcript_exon_variant | 2/3 | 4 | ||||
NPC1 | ENST00000591955.1 | n.362C>G | non_coding_transcript_exon_variant | 1/2 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.000197 AC: 30AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000123 AC: 31AN: 251490Hom.: 0 AF XY: 0.0000956 AC XY: 13AN XY: 135918
GnomAD4 exome AF: 0.000168 AC: 246AN: 1461864Hom.: 0 Cov.: 31 AF XY: 0.000176 AC XY: 128AN XY: 727234
GnomAD4 genome ? AF: 0.000197 AC: 30AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74428
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C1 Pathogenic:15Uncertain:1Other:1
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 27, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 28, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 24, 2023 | Identified as compund heterozygous with NM_000271.5:c.1997G>A. Criteria applied: PM3_VSTR,PM5,PM2_SUP,PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Sep 09, 2022 | ACMG classification criteria: PS4 strong, PM2 supporting, PM3 very strong, PP1 supporting, PP3 supporting - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | Nov 03, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 28, 2018 | 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] - |
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Aug 02, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 24, 2019 | 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 - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Inherited Metabolic Diseases, Karolinska University Hospital | Apr 07, 2021 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | 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. - |
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 04, 2014 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2021 | 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) - |
Niemann-Pick disease, type C Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 26, 2017 | 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. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 12, 2021 | 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. - |
NPC1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 21, 2023 | 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. - |
Cataplexy;C0007758:Cerebellar ataxia;C0018681:Headache;C0264611:Speech apraxia;C0338656:Cognitive impairment;C1843921:Postural instability Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 07, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at