rs1190383931

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000271.5(NPC1):ā€‹c.1526A>Cā€‹(p.Tyr509Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,776 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).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000082 ( 0 hom. )

Consequence

NPC1
NM_000271.5 missense

Scores

10
8
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 3.88
Variant links:
Genes affected
NPC1 (HGNC:7897): (NPC intracellular cholesterol transporter 1) This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.[provided by RefSeq, Aug 2009]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a topological_domain Lumenal (size 248) in uniprot entity NPC1_HUMAN there are 30 pathogenic changes around while only 10 benign (75%) in NM_000271.5
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
Variant 18-23554785-T-G is Pathogenic according to our data. Variant chr18-23554785-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 554002.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NPC1NM_000271.5 linkc.1526A>C p.Tyr509Ser missense_variant 9/25 ENST00000269228.10 NP_000262.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NPC1ENST00000269228.10 linkc.1526A>C p.Tyr509Ser missense_variant 9/251 NM_000271.5 ENSP00000269228.4 O15118-1
NPC1ENST00000591051.1 linkc.806A>C p.Tyr269Ser missense_variant 4/182 ENSP00000467636.1 K7EQ23
NPC1ENST00000540608.5 linkn.1440A>C non_coding_transcript_exon_variant 7/162
NPC1ENST00000590301.1 linkn.201A>C non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461776
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727204
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylSep 22, 2017- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 04, 2023This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr509 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 22676771), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 554002). This missense change has been observed in individuals with Niemann-Pick disease type C (PMID: 26666848, 30202070; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 509 of the NPC1 protein (p.Tyr509Ser). -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 06, 2024Variant summary: NPC1 c.1526A>C (p.Tyr509Ser) results in a non-conservative amino acid change located in the NPC1, middle luminal domain (IPR053956) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251406 control chromosomes. c.1526A>C has been reported in the literature in the heterozygous (2nd allele not specified), presumed compound heterozygous, and compound heterozygous state in multiple individuals affected with Niemann-Pick Disease Type C (example, Garver_2010, Imrie_2015, Park_2003). These data indicate that the variant may be associated with disease. Three publications report experimental evidence evaluating an impact on protein function in a human fibroblast cell line carrying a 2nd pathogenic allele in trans, however the impact of this variant alone could not be determined (example, Pepponi_2022, Schultz_2018, Yu_2012). The following publications have been ascertained in the context of this evaluation (PMID: 19744920, 26666848, 12955717, 35408815, 30202070, 22505584). ClinVar contains an entry for this variant (Variation ID: 554002). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.84
D
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.95
D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.3
M
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-6.3
D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0080
D
Polyphen
0.73
P
Vest4
0.79
MutPred
0.86
Loss of sheet (P = 0.0315);
MVP
0.91
MPC
0.98
ClinPred
0.99
D
GERP RS
3.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1190383931; hg19: chr18-21134749; API