chr8-43173740-C-T

Position:

chr8-43173740-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_152419.3(HGSNAT):c.848C>T(p.Pro283Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,612,400 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P283S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

HGSNAT
NM_152419.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.02

Variant links:

Genes affected

HGSNAT (HGNC:26527): (heparan-alpha-glucosaminide N-acetyltransferase) This gene encodes a lysosomal acetyltransferase, which is one of several enzymes involved in the lysosomal degradation of heparin sulfate. Mutations in this gene are associated with Sanfilippo syndrome C, one type of the lysosomal storage disease mucopolysaccaridosis III, which results from impaired degradation of heparan sulfate. [provided by RefSeq, Jan 2009]

HGSNAT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity HGNAT_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_152419.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-43173739-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1488117.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 8-43173740-C-T is Pathogenic according to our data. Variant chr8-43173740-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-43173740-C-T is described in Lovd as [Pathogenic]. Variant chr8-43173740-C-T is described in Lovd as [Pathogenic]. Variant chr8-43173740-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HGSNAT	NM_152419.3 linkuse as main transcript	c.848C>T	p.Pro283Leu	missense_variant	9/18	ENST00000379644.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HGSNAT	ENST00000379644.9 linkuse as main transcript	c.848C>T	p.Pro283Leu	missense_variant	9/18	2	NM_152419.3	P3	Q68CP4-2
HGSNAT	ENST00000520704.1 linkuse as main transcript	c.*297C>T		3_prime_UTR_variant, NMD_transcript_variant	10/10	1
HGSNAT	ENST00000522082.5 linkuse as main transcript	c.89C>T	p.Pro30Leu	missense_variant	2/6	4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000283

AC:

AN:

246918

Hom.:

AF XY:

0.0000373

AC XY:

AN XY:

133948

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000168

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1460284

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726294

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000901

Hom.:

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 283 of the HGSNAT protein (p.Pro283Leu). This variant is present in population databases (rs121908282, gnomAD 0.02%). This missense change has been observed in individuals with Mucopolysaccharidosis IIIC (Sanfilippo C Syndrome) (PMID: 17033958, 31228227). This variant is also known as P311L. ClinVar contains an entry for this variant (Variation ID: 1232). 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 HGSNAT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HGSNAT function (PMID: 19823584, 20583299). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 03, 2022	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2017	The P283L variant in the HGSNAT gene has been reported previously, using alternate nomenclature P311L, in association with mucopolysaccharidosis IIIC, in an affected individual who was homozygous for the P283L variant, and in an affected individual who was heterozygous for the P283L variant and another HGSNAT variant (Hrebicek et al., 2006). The P283L variant is observed in 3/18754 (0.016%) alleles from individuals of East Asian background, in the ExAC dataset (Lek et al., 2016). The P283L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies show that P283L has reduced enzyme activity compared to wild type and mislocalization due to incorrect protein folding (Feldhammer et al., 2009; Fedele et al., 2010). We interpret P283L as a likely pathogenic variant. -

Retinal dystrophy

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Likely pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

Mucopolysaccharidosis, MPS-III-C

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2006

- -

Sanfilippo syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 18, 2023

Variant summary: HGSNAT c.848C>T (p.Pro283Leu) results in a non-conservative amino acid change located in the catalytic domain (IPR012429) of 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 2.8e-05 in 246918 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.848C>T has been reported in the literature in both homozygous and compound heterozygous individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) (e.g., Hrebicek_2006, Martins_2019). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal activity (e.g., Feldhammer_2009, Fedele_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20583299, 19823584, 17033958, 31228227). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.1

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-9.0

D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Vest4

0.97

MVP

0.94

MPC

0.53

ClinPred

0.97

GERP RS

5.2

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over