chr8-43161462-G-A

Position:

• chr8-43161462-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_152419.3(HGSNAT):​c.518G>A​(p.Gly173Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HGSNAT NM_152419.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 2.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a topological_domain Lumenal, vesicle (size 189) in uniprot entity HGNAT_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_152419.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814
• PP5: Variant 8-43161462-G-A is Pathogenic according to our data. Variant chr8-43161462-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 252961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-43161462-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HGSNAT	NM_152419.3	c.518G>A	p.Gly173Asp	missense_variant	5/18	ENST00000379644.9	NP_689632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HGSNAT	ENST00000379644.9	c.518G>A	p.Gly173Asp	missense_variant	5/18	2	NM_152419.3	ENSP00000368965	P3
HGSNAT	ENST00000520704.1	c.368G>A	p.Gly123Asp	missense_variant, NMD_transcript_variant	5/10	1		ENSP00000429109
HGSNAT	ENST00000517319.1	c.*87G>A		3_prime_UTR_variant, NMD_transcript_variant	4/5	4		ENSP00000430032

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-C Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 01, 2020	Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS3,PM2,PM3_Strong -
Pathogenic, criteria provided, single submitter	clinical testing;in vitro	Charité Universitätsmedizin Berlin, Charite Universitaetsmedizin Berlin	Aug 03, 2016	The effect of the mutation has been verified by a biochemical assay in one affected (homozygous) patient: measurement of Heparan-alpha-glucosaminide-N-acetyltransferase activity. Patient: 0.09 nmol/h*mg; controls 0.2-1.3 nmol/h*mg, n=11 -

Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 14, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HGSNAT function (PMID: 31228227). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HGSNAT protein function. ClinVar contains an entry for this variant (Variation ID: 252961). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 27827379, 31228227). 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 173 of the HGSNAT protein (p.Gly173Asp). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2024

Published functional studies demonstrate a damaging effect on enzymatic activity, processing, cellular localization, and expression (PMID: 31228227); 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: 28097321, 27827379, 31228227) -

Sanfilippo syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jul 30, 2024

Variant summary: HGSNAT c.518G>A (p.Gly173Asp) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 247464 control chromosomes. c.518G>A has been reported in the literature in compound heterozygous and homozygous individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C) (e.g. Hu_2017, Martins_2019). 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 severely reduced enzyme activity in vitro and in homozygous patient fibroblasts (e.g. Hu_2017, Martins_2019). The following publications have been ascertained in the context of this evaluation (PMID: 27827379, 31228227). ClinVar contains an entry for this variant (Variation ID: 252961). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mucopolysaccharidosis Other:1

not provided, no classification provided

literature only

GeneReviews

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	0.017
Eigen_PC	Benign	0.023
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.33	D
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.49
Sift	Benign	0.040	D
Sift4G	Benign	0.21	T
Vest4		0.89
MVP		0.91
MPC		0.32
ClinPred		0.68	D
GERP RS		4.5
gMVP		0.87

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: rs370717845; hg19: chr8-43016605;