rs778336949
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong
The NM_000199.5(SGSH):c.221G>A(p.Arg74His) variant causes a missense change. The variant allele was found at a frequency of 0.0000044 in 1,590,362 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. R74C) has been classified as Pathogenic.
Frequency
Consequence
NM_000199.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SGSH | NM_000199.5 | c.221G>A | p.Arg74His | missense_variant | 2/8 | ENST00000326317.11 | NP_000190.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SGSH | ENST00000326317.11 | c.221G>A | p.Arg74His | missense_variant | 2/8 | 1 | NM_000199.5 | ENSP00000314606 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000417 AC: 6AN: 1437992Hom.: 0 Cov.: 31 AF XY: 0.00000420 AC XY: 3AN XY: 713484
GnomAD4 genome AF: 0.00000656 AC: 1AN: 152370Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74500
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-A Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 17, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 74 of the SGSH protein (p.Arg74His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with MPS IIIA (PMID: 9401012, 11343308; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 550504). 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 95%. This variant disrupts the p.Arg74 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9285796, 9401012, 11343308, 22976768, 28844463). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 30, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2021 | Variant summary: SGSH c.221G>A (p.Arg74His) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) 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 4.7e-06 in 211504 control chromosomes (gnomAD and publication data). c.221G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A), including at least two homozygotes (Bunge_1997, Chabas_2001, Montfort_2004). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant results in reducing sulfamidase activity compared to WT activity (Montfort_2004). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=1) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova | Jan 01, 2019 | PS3: Low in vitro enzymatic activity. PM2: Absent from GnomAD - |
SGSH-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 17, 2024 | The SGSH c.221G>A variant is predicted to result in the amino acid substitution p.Arg74His. This variant, also referred to as R74H, has been reported in the homozygous state in several individuals with a diagnosis or clinical features suggestive of mucopolysaccharidosis type IIIA (MPS IIIA), also known as Sanfilippo syndrome A (Bunge et al. 1997. PubMed ID: 9401012; Chabás et al. 2001. PubMed ID: 11343308; Gul et al. 2023. PubMed ID: 37772257). It was also reported along with a second pathogenic SGSH variant in a patient with MPS IIIA (Chabás et al. 2001. PubMed ID: 11343308). A different missense change impacting the same amino acid (c.220C>T; p.Arg74Cys) has been reported in individuals with MPS IIIA (Weber et al. 1997. PubMed ID: 9285796; Yassaee et al. 2017. PubMed ID: 28844463). This amino acid residue is highly conserved and is a critical component to the protein's active site; changes to this amino acid result in decreased enzyme stability and disruption of ion binding (Sidhu et al. 2014. PubMed ID: 24816101). This variant is reported in 0.0037% of alleles in individuals of South Asian descent in gnomAD; however, the quality of this data is questionable and should be treated with caution. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 21, 2023 | Published functional studies demonstrate that the variant results in significantly decreased enzyme activity (PMID: 15542396); 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: 24816101, 16174644, 9401012, 15542396) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at