ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3019C>G (p.Pro1007Ala) (rs80358257)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254671 SCV000208910 pathogenic not provided 2018-03-12 criteria provided, single submitter clinical testing The P1007A variant has been previously reported in association with Niemann-Pick disease, type C both in the homozygous state and in the presence of another pathogenic variant (Synofzik et al., 2015; Reunert et al., 2016; Szakszon et al., 2014). The P1007A variant is observed in 28/126,720 (0.022%) alleles from individuals of European (non-Finnish) background, in large population cohorts, and no homozygous individuals were observed (Lek et al., 2016). The P1007A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we interpret P1007A as a pathogenic variant.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000254671 SCV000227615 pathogenic not provided 2014-12-04 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 2019-10-28 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 1007 of the NPC1 protein (p.Pro1007Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs80358257, ExAC 0.02%). This variant has been reported as homozygous and in combination with other NPC1 variants in multiple individuals affected with Niemann-Pick Type C disease with evidence of co-segregation in a family (PMID: 23791518, 23183285, 14639697, 26981555, 25425405, 10521290, 11754101). It is one of the prevalent NPC1 mutations in western Europeans and has been associated with a "biochemical variant" phenotype and adult onset of the disease (PMID: 26981555, 20525256,11333381, 11479732, 17003072). ClinVar contains an entry for this variant (Variation ID: 2966). Experimental studies of cells from NPC patients have associated this variant with depressed cholesterol esterification and exosome secretion (PMID: 12955717 , 20554533). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. However, existing data from recombinant mutant protein do not indicate that the variant has a strong functional impact (PMID: 15937921). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America 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.
DNA and Cytogenetics Diagnostics Unit,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 Women's Health, 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 Praxis fuer Humangenetik Tuebingen RCV000254671 SCV001249523 pathogenic not provided 2018-07-01 criteria provided, single submitter clinical testing
OMIM RCV000003100 SCV000023258 pathogenic Niemann-Pick disease type C1 2001-06-01 no assertion criteria provided literature only
GeneReviews RCV000003100 SCV000040575 pathologic Niemann-Pick disease type C1 2008-07-22 no assertion criteria provided curation Converted during submission to Pathogenic.
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,VU University Medical Center Amsterdam RCV000003100 SCV000745697 likely pathogenic Niemann-Pick disease type C1 2016-11-03 no assertion criteria provided clinical testing

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