rs752914124

Variant names:

• chr17-80210678-CGGAGGTCCTTG-C
• rs752914124
• NM_000199.5:c.1272_1282delCAAGGACCTCC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000199.5(SGSH):​c.1272_1282delCAAGGACCTCC​(p.Tyr424fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000691 in 1,461,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: SGSH NM_000199.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.13

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 14 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 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-80210678-CGGAGGTCCTTG-C is Pathogenic according to our data. Variant chr17-80210678-CGGAGGTCCTTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 287037.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
SGSH	NM_000199.5	c.1272_1282delCAAGGACCTCC	p.Tyr424fs	frameshift_variant	Exon 8 of 8	ENST00000326317.11	NP_000190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11	c.1272_1282delCAAGGACCTCC	p.Tyr424fs	frameshift_variant	Exon 8 of 8	1	NM_000199.5	ENSP00000314606.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250606 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135776

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000691 AC: 101 AN: 1461730 Hom.: 0 AF XY: 0.0000646 AC XY: 47 AN XY: 727156

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Pathogenic:8

May 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 12, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 2021

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.1272_1282del11 (p.Tyr424X) 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. Truncations downstream of this position have not been classified as pathogenic by our laboratory but have been reported in the HGMD database with a reported phenotype of Sanfillipo syndrome A. The variant allele was found at a frequency of 4e-06 in 250606 control chromosomes. c.1272_1282del11 has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (example, Scott_1997, Weber_1997). 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. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 27, 2018

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2024

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.Tyr424*) in the SGSH gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the SGSH protein. This variant is present in population databases (rs752914124, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with SGSH-related conditions (PMID: 7493035, 27590925). ClinVar contains an entry for this variant (Variation ID: 287037). This variant disrupts a region of the SGSH protein in which other variant(s) (p.Trp471*) have been determined to be pathogenic (internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Mar 25, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1272_1282del11 variant in the SGSH gene has been reported previously in association with Sanfilippo Syndrome A, also known as MPS IIIA (Scott et al., 1995; Truxal et al., 2016). It is reported as pathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available (ClinVar SCV000340680.2; Landrum et al., 2016). The c.1272_1282del11 variant causes a frameshift, changing codon Tyrosine 424 to a premature Stop codon, which eliminates the last 79 amino acids from the protein, and is denoted p.Tyr424Ter. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1272_1282del11 variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.1272_1282del11 as a pathogenic variant. -

Diarrhea;C0028738:Nystagmus;C0557874:Global developmental delay;C0854723:Retinal dystrophy;C1301509:Severely reduced visual acuity;C1836830:Developmental regression;C1836923:Gastrointestinal dysmotility Pathogenic:1

-

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Inborn genetic diseases Pathogenic:1

Jul 22, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1272_1282del11 (p.Y424*) alteration, located in exon 8 (coding exon 8) of the SGSH gene, consists of a deletion of 11 nucleotides from position 1272 to 1282, causing a translational frameshift with a predicted alternate stop codon after amino acids. This alteration occurs at the 3' terminus of the SGSH gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 15.5% of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/250606) total alleles studied. The highest observed frequency was <0.001% (1/113066) of European (non-Finnish) alleles. This variant has been identified in conjunction with other SGSH variants in individuals with reduced enzyme activity and/or a diagnosis of mucopolysaccharidosis type IIIA (H&eacute;ron, 2011; Truxal, 2016; Sahajpal, 2023). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752914124; hg19: chr17-78184477;