rs770947426

Variant names:

• chr17-80210880-CG-C
• rs770947426
• NM_000199.5:c.1080delC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000199.5(SGSH):​c.1080delC​(p.Val361SerfsTer52) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,612,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T360T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SGSH NM_000199.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: -3.75
• Publications: 8 publications found

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]

CARD14 Gene-Disease associations (from GenCC):

• familial pityriasis rubra pilaris

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• psoriasis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 65 pathogenic variants in the truncated region.
• PP5: Variant 17-80210880-CG-C is Pathogenic according to our data. Variant chr17-80210880-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 518268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000199.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSH	NM_000199.5	MANE Select	c.1080delC	p.Val361SerfsTer52	frameshift	Exon 8 of 8	NP_000190.1
	SGSH	NR_148201.2		n.994delC		non_coding_transcript_exon	Exon 7 of 7
	SGSH	NM_001352921.3		c.*167delC		3_prime_UTR	Exon 8 of 8	NP_001339850.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSH	ENST00000326317.11	TSL:1 MANE Select	c.1080delC	p.Val361SerfsTer52	frameshift	Exon 8 of 8	ENSP00000314606.6
	SGSH	ENST00000575282.5	TSL:1	n.3963delC		non_coding_transcript_exon	Exon 5 of 5
	SGSH	ENST00000573150.5	TSL:2	n.*290delC		non_coding_transcript_exon	Exon 7 of 7	ENSP00000459280.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000721 AC: 18 AN: 249790 AF XY: 0.0000887

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000974

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1460682 Hom.: 0 Cov.: 34 AF XY: 0.000127 AC XY: 92 AN XY: 726588

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000134 AC: 6 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000137 AC: 152 AN: 1111972

Other (OTH) AF: 0.0000497 AC: 3 AN: 60374

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41552

American (AMR) AF: 0.000196 AC: 3 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Pathogenic:12

Sep 14, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SGSH c.1080delC (p.Val361SerfsX52) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.5e-05 in 275896 control chromosomes (gnomAD). This frequency is lower than expected for a pathogenic variant in SGSH causing Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (6.5e-05 vs 0.0032), allowing no conclusion about variant significance. The variant, c.1080delC, has been reported in the literature in multiple individuals (inlcuding homozygotes) affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A), being one of the most frequent variants associated with the disease (Montfort 2004, Heron 2010). At least two publications reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Montfort 2004, Heron 2010). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 03, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected; Variant is present in gnomAD <0.01 for a recessive condition (v4: 171 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar; Other protein truncating variant(s) comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). Additional information: This variant is heterozygous; This gene is associated with autosomal recessive disease; Loss of function is a known mechanism of disease in this gene and is associated with mucopolysaccharidosis type IIIA (Sanfilippo A) (MIM#252900); Heterozygous variant detected in trans with a second PATHOGENIC heterozygous variant (NM_000199.5(SGSH):c.734G>A; p.(Arg245His)) in a recessive disease; This variant has been shown to be maternally inherited by trio analysis.

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val361Serfs*52) in the SGSH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 142 amino acid(s) of the SGSH protein. This variant is present in population databases (rs770947426, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with mucopolysaccharidosis type III (PMID: 9285796, 15542396, 21061399, 21910976, 22976768). This variant is also known as c.1091delC and delC1091. ClinVar contains an entry for this variant (Variation ID: 518268). For these reasons, this variant has been classified as Pathogenic.

Mar 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 20, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000518268 /PMID: 9285796). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Jan 01, 2019

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

PVS1: frameshift. PS3: Low in vitro enzymatic acitivity. PM2: Absent from GnomAD

May 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:3

Oct 15, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies of the c.1080delC variant demonstrate reduced enzyme activity (Montfort et al., 2004); Frameshift variant predicted to result in protein truncation, as the last 142 amino acids are replaced with 51 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22976768, 9285796, 31536183, 28451919, 15542396, 21228398, 26918231, 26787381, 27590925, 29023963, 21910976, 21061399, 30809705, 11343308, 11182930, 9744479, 34440436, 34349725, 31589614)

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SGSH: PM3:Very Strong, PVS1:Strong, PM2, PS3:Supporting

Mucopolysaccharidosis Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.8
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs770947426; hg19: chr17-78184679; COSMIC: COSV108155248; COSMIC: COSV108155248;