rs80358258

Variant names:

• chr18-23536758-C-T
• rs80358258
• NM_000271.5:c.3160G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000271.5(NPC1):​c.3160G>A​(p.Ala1054Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,870 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 6.03

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a topological_domain Lumenal (size 243) in uniprot entity NPC1_HUMAN there are 84 pathogenic changes around while only 9 benign (90%) in NM_000271.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 18-23536758-C-T is Pathogenic according to our data. Variant chr18-23536758-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.3160G>A	p.Ala1054Thr	missense_variant	Exon 21 of 25	ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.3160G>A	p.Ala1054Thr	missense_variant	Exon 21 of 25	1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.2236G>A	p.Ala746Thr	missense_variant	Exon 14 of 18	2		ENSP00000467636.1
NPC1	ENST00000591075.1	n.793G>A		non_coding_transcript_exon_variant	Exon 3 of 3	4
NPC1	ENST00000591955.1	n.503G>A		non_coding_transcript_exon_variant	Exon 2 of 2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251446 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Niemann-Pick disease, type C1 Pathogenic:1 Other:1

Oct 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1054 of the NPC1 protein (p.Ala1054Thr). This variant is present in population databases (rs80358258, gnomAD 0.01%). This missense change has been observed in individual(s) with Niemann-Pick type C disease (PMID: 11333381, 20718790). ClinVar contains an entry for this variant (Variation ID: 21138). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NPC1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Niemann-Pick disease, type C Pathogenic:1

Apr 11, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NPC1 c.3160G>A (p.Ala1054Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251446 control chromosomes. c.3160G>A has been reported in the literature in at-least three individuals affected with Niemann-Pick Disease Type C (Havla_2020, Millat_2001, Stampfer_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in almost absence of NPC1 protein in skin cells from the patient carrying the homozygous variant (Millat_2001).The following publications have been ascertained in the context of this evaluation (PMID: 32222928, 11333381, 23433426). ClinVar contains an entry for this variant (Variation ID: 21138). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

May 09, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 11333381, 28472934, 32222928, 37433892, 20301473, 20718790) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.86		Loss of ubiquitination at K1057 (P = 0.141);
MVP		0.95
MPC		0.89
ClinPred		0.94	D
GERP RS		5.9
Varity_R		0.65
gMVP		0.94

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

Other links and lift over

dbSNP: rs80358258; hg19: chr18-21116722;