ClinVar Genomic variation as it relates to human health

The SGSH c.1339G>A (p.Glu447Lys) variant has been reported in three studies and is found in a total of five individuals with mucopolysaccharidosis including two in a homozygous state and three in a compound heterozygous state (including two siblings who carried a canonical splice site (donor) variant on the second allele) (Blanch et al. 1997; Chabas et al. 2001; Shapiro et al. 2016). The p.Glu447Lys variant was absent from 120 control alleles (Blanch et al. 1997) and is reported at a frequency of 0.00002 in the total population of the Exome Aggregation Consortium. Based on the evidence, the p.Glu447Lys variant is classified as likely pathogenic for mucopolysaccharidosis, type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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: 18254660, 21228398, 25807448, 30809705, 11668611, 24347096, 24816101, 19099774, 11343308, 9158154)

A Homozygote Missense variant c.1339G>A in Exon 8 of the SGSH gene that results in the amino acid substitution p.Glu447Lys was identified. The observed variant has a maximum allele frequency of 0.00007/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic and LikelyPathogenic (Variant ID: 5114). This variant was reported among patients affected by mucopolysaccharidosis (Zanetti A et al, 2010). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 447 of the SGSH protein (p.Glu447Lys). This variant is present in population databases (rs104894639, gnomAD 0.04%). This missense change has been observed in individual(s) with mucopolysaccharidosis (MPS) type IIIA (PMID: 9158154, 19099774, 26787381; 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: 5114). 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%. For these reasons, this variant has been classified as Pathogenic.

PS3: Low in vivo enzymatic activity in homozygotes; PM2: Very low frequency in GnomAD

The homozygous missense variation in exon 8 of SGSH gene that results in the amino acid substitution to lysine for glutamic acis at codon of 447 was detected. The variant c.1339G>A (p.Glu447Lys) has not been reported in 1000 genome and has a MAF of 0.007% in the gnomAD database. The insilico prediction of the variant is dIsease causing by MutationTaster, CADD , PROVEAN and SIFT.

The c.1339G>A (p.E447K) alteration is located in exon 8 (coding exon 8) of the SGSH gene. This alteration results from a G to A substitution at nucleotide position 1339, causing the glutamic acid (E) at amino acid position 447 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (18/281098) total alleles studied. The highest observed frequency was 0.04% (13/35374) of Latino alleles. This alteration has been detected in the homozygous state and as compound heterozygous with other pathogenic SGSH alterations in multiple unrelated individuals with Sanfilippo syndrome (Chabas, 2001; Matalonga, 2014; Blanch, 1997; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, E447K is deleterious and moderately destabilizing to the local structure (Sidhu, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.