17-80210831-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000199.5(SGSH):c.1130G>A(p.Arg377His) variant causes a missense change. The variant allele was found at a frequency of 0.0000161 in 1,613,840 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. R377C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: SGSH NM_000199.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.03

Genes affected

SGSH (HGNC:10818): (N-sulfoglucosamine sulfohydrolase) This gene encodes the enzyme sulfamidase; one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with the lysosomal storage disease mucopolysaccaridosis IIIA, also known as Sanfilippo syndrome A, which results from impaired degradation of heparan sulfate. Transcripts of varying sizes have been reported but their biological validity has not been determined. [provided by RefSeq, Jun 2017]

CARD14 (HGNC:16446): (caspase recruitment domain family member 14) This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000199.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80210832-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-80210831-C-T is Pathogenic according to our data. Variant chr17-80210831-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1297691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80210831-C-T is described in Lovd as [Pathogenic]. Variant chr17-80210831-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGSH	NM_000199.5	c.1130G>A	p.Arg377His	missense_variant	8/8	ENST00000326317.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGSH	ENST00000326317.11	c.1130G>A	p.Arg377His	missense_variant	8/8	1	NM_000199.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250948 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

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: 0.0000171 AC: 25 AN: 1461668 Hom.: 0 Cov.: 34 AF XY: 0.0000179 AC XY: 13 AN XY: 727122

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 377 of the SGSH protein (p.Arg377His). This variant is present in population databases (rs746037899, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis IIIA (PMID: 29023963, 31718697). ClinVar contains an entry for this variant (Variation ID: 1297691). 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 SGSH protein function with a positive predictive value of 80%. This variant disrupts the p.Arg377 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9554748, 12000360, 19099774, 21910976). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2022	Variant summary: SGSH c.1130G>A (p.Arg377His) results in a non-conservative amino acid change in the encoded protein sequence. This variant is predicted to impact the structure of the SGSH protein due to loss of a buried salt bridge with Asp 477 and of hydrogen bonds to Ser 366 and Met 376 (Sidhu_2014). 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 4e-06 in 250948 control chromosomes. c.1130G>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (example, Bunge_1997, Valstar_2010, Knottnerus_2017, Nijmeijer_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Aug 08, 2022	A compound heterozygous missense variation in exon 8 and exon 7 of the SGSH gene that results in the amino acid substitution of Histidine for Arginine at codon377 was detected. The observed variant c.1130G>A(p.Arg377His) has a minor allele frequency of 0.0003%, and 0.0008% in the 1000 genomes and gnomAD databases. Alternative variant chr17:78184631 G⇒A (Arg377Cys) is classified Pathogenic by UniProt Variants (and confirmed using ACMG). The in silico prediction of the variant is benign by DANN, SIFT, LRT ,FATHMM-XF, MutPred and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 16, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -

not provided Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.98		Loss of sheet (P = 0.0181);
MVP		0.92
MPC		0.86
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs746037899; hg19: chr17-78184630;