rs374621913
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000199.5(SGSH):c.697C>T(p.Arg233*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000305 in 1,608,344 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000199.5 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152232Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000127 AC: 3AN: 236656Hom.: 0 AF XY: 0.00000776 AC XY: 1AN XY: 128828
GnomAD4 exome AF: 0.0000309 AC: 45AN: 1456112Hom.: 0 Cov.: 31 AF XY: 0.0000345 AC XY: 25AN XY: 724200
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74376
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-A Pathogenic:7
- -
This sequence change creates a premature translational stop signal (p.Arg233*) in the SGSH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGSH are known to be pathogenic (PMID: 11182930, 21204211, 22976768). 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 premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 15146460). ClinVar contains an entry for this variant (Variation ID: 370732). For these reasons, this variant has been classified as Pathogenic. -
- -
- -
- -
- -
- -
Inborn genetic diseases Pathogenic:1
The c.697C>T (p.R233*) alteration, located in exon 6 (coding exon 6) of the SGSH gene, consists of a C to T substitution at nucleotide position 697. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 233. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (4/268038) total alleles studied. The highest observed frequency was 0.006% (2/34596) of Latino alleles. This alteration was detected, in conjunction with another alteration in SGSH, in multiple individuals with Mucopolysaccharidosis type IIIA (Beesley, 2000; Ghosh, 2021). Based on the available evidence, this alteration is classified as pathogenic. -
not provided Pathogenic:1
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34426522, Natalia2015[Abstract], 34047372, 11182930, 15146460) -
Sanfilippo syndrome Pathogenic:1
Variant summary: The c.697C>T (p.Arg233*) variant in SGSH gene is a nonsense change that results in the loss of the ~54% of the length of the protein (270 aa). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay, which was proven by RNA and protein expression studies (Muschol, 2004). The variant is present in the large control population dataset of ExAC at a low frequency 1.1e-05 (1/90902 chrs tested). This frequency does not exceed the maximal expected frequency of a pathogenic allele (0.0032 in this gene. The variant of interest has been reported in numerous affected individual homozygously or in compound heterozygous state. In addition, the variant is cited as Pathogenic by multiple reputable database/diagnostic centers. Taking together, the variant was classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at