rs150334966

chr18-23538572-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1 PP5 BP4 BS1_Supporting

The NM_000271.5(NPC1):c.3011C>T(p.Ser1004Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000728 in 1,614,152 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1004S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (2 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:6
• Conservation: PhyloP100: 8.06

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000271.5
• PP5: Variant 18-23538572-G-A is Pathogenic according to our data. Variant chr18-23538572-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 326253.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=5}. Variant chr18-23538572-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.3705725).. Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000736 (1076/1461878) while in subpopulation EAS AF= 0.00448 (178/39698). AF 95% confidence interval is 0.00395. There are 2 homozygotes in gnomad4_exome. There are 532 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPC1	NM_000271.5	c.3011C>T	p.Ser1004Leu	missense_variant	20/25	ENST00000269228.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPC1	ENST00000269228.10	c.3011C>T	p.Ser1004Leu	missense_variant	20/25	1	NM_000271.5	P1
NPC1	ENST00000591051.1	c.2090C>T	p.Ser697Leu	missense_variant	13/18	2
NPC1	ENST00000591075.1	n.644C>T		non_coding_transcript_exon_variant	2/3	4
NPC1	ENST00000591955.1	n.354C>T		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000684 AC: 172 AN: 251486 Hom.: 0 AF XY: 0.000728 AC XY: 99 AN XY: 135918

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000736 AC: 1076 AN: 1461878 Hom.: 2 Cov.: 31 AF XY: 0.000732 AC XY: 532 AN XY: 727238

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00448

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00157

Gnomad4 NFE exome AF: 0.000688

Gnomad4 OTH exome AF: 0.000596

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74456

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000881 Hom.: 0

Bravo AF: 0.000468

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:3 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The NPC1 gene c.3011C>T (p.Ser1004Leu) variant is a missense variant that is reported in two studies and found in a total of three individuals, including a sibling pair, with Niemann-Pick disease (NPC), all in a compound heterozygous state (Sun et al. 2001; Kawazoe et al. 2018). In the sibling pair, the p.Ser1004Leu variant was inherited from an unaffected father and was in trans with a frameshift variant inherited from the mother (Kawazoe et al. 2018). Control data are not available but the variant is reported at a frequency of 0.002268 in the European (Finnish) population of the Exome Aggregation Consortium. The Ser 1004 residue is located within the cysteine-rich region of the protein. Filipin staining of skin fibroblasts from one of the patients showed a staining pattern associated with NPC (Kawazoe et al. 2018). The evidence for this variant is limited. The p.Ser1004Leu variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Niemann-Pick disease. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1004 of the NPC1 protein (p.Ser1004Leu). This variant is present in population databases (rs150334966, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 11349231, 30119649; Invitae). 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: 326253). 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%. This variant disrupts the p.Ser1004 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in individuals with NPC1-related conditions (PMID: 32222928), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 11, 2017	- -

not provided Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	NPC1: PM2, PM3, PM5, PP3, PS4:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11349231, 24386122, 30119649, 32371106) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 28, 2024

Variant summary: NPC1 c.3011C>T (p.Ser1004Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 251486 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NPC1 causing Niemann-Pick Disease Type C (0.00068 vs 0.0027), allowing no conclusion about variant significance. c.3011C>T has been reported in the literature as a biallelic compound heterozygous genotype in individuals with a clinically variable phenotype of Niemann-Pick disease type C (NPC) (example, Kawazoe_2018, Sun_2001). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30119649, 11349231). ClinVar contains an entry for this variant (Variation ID: 326253). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

NPC1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2024

The NPC1 c.3011C>T variant is predicted to result in the amino acid substitution p.Ser1004Leu. This variant has been reported in patients with Niemann-Pick disease, however, its pathogenicity was not completely elucidated (Sun et al. 2001. PubMed ID: 11349231; Kawazoe et al. 2018. PubMed ID: 30119649). This variant is reported in 0.15% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretation in ClinVar ranging from uncertain to likely pathogenic (https://preview.ncbi.nlm.nih.gov/clinvar/variation/326253/). Of note, a different variant impacting the same amino acid (p.Ser1004Pro) has been documented in patients with NPC1-related disorder (Supplemental Table 1 in Reunert. 2016. PubMed ID: 26981555). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.76
Sift	Benign	0.062	T
Sift4G	Benign	0.16	T
Polyphen		0.84	P
Vest4		0.93
MVP		0.95
MPC		0.29
ClinPred		0.17	T
GERP RS		5.4
Varity_R		0.49
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs150334966; hg19: chr18-21118536; COSMIC: COSV52578837; COSMIC: COSV52578837;