Submissions for variant NM_000199.5(SGSH):c.1063G>A (p.Glu355Lys)

gnomAD frequency: 0.00004  dbSNP: rs766938111

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000489539	SCV000407353	uncertain significance	Mucopolysaccharidosis, MPS-III-A	2018-05-07	criteria provided, single submitter	clinical testing	The SGSH c.1063G>A (p.Glu355Lys) variant has been reported in a compound heterozygous state with a frameshift variant in one individual with mucopolysaccharidosis type 3 described as having very low or no detectable sulphamidase enzyme activity in leucocytes (Beesley et al. 2000). The p.Glu355Lys variant was also identified in a compound heterozygous state with a second missense variant in an individual with adult neuronal ceroid lipofuscinosis and absent protein (Sleat et al. 2009). The p.Glu355Lys variant was absent from 100 control chromosomes and is reported at a frequency of 0.00003 in the total population of the Exome Aggregation Consortium. Analysis of the crystal structure of glycosylated SGSH suggested that the p.Glu355Lys variant results in the loss of a surface salt bridge and hydrogen bonds (Sidhu et al. 2014). The p.Glu355Lys variant results in a non-conservative amino acid substitution, which occurs at a position that is conserved across species. The evidence for this variant is limited. The p.Glu355Lys variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for mucopolysaccharidosis, type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000414288	SCV000491270	pathogenic	not provided	2022-08-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25807448, 11668611, 31718697, 24816101, 11182930, 19383612, 21990111)
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000489539	SCV000575935	pathogenic	Mucopolysaccharidosis, MPS-III-A	2017-04-26	criteria provided, single submitter	clinical testing	The following ACMG criteria are met: PS3 (Well-established functional study), PM2 (Absent or very low frequency in population databases), PM3 (In trans with pathogenic variant, Beesley 2000), PP1 (Co-segregation with disease in multiple family members), PP3 (Multiple lines of computational evidence support deleterious effect). This variant has been reported previously in trans in a patient with confirmed MPS IIIA based on clinical features and enzyme activity. Two sisters in our clinical practice are compound heterozygotes for E355K and P225L and a clinical diagnosis of MPS IIIA was confirmed by clinical exam, positive urine screen, and absent enzyme activity in leukocytes. The younger sister has global developmental delays, autism spectrum disorder, sensorineural hearing loss, myopia, astigmatism, and a seizure disorder. The older sister has intellectual disability, autism spectrum disorder, sensorineural hearing loss, myopia, astigmatism, recurrent otitis media, precocious puberty, and seizure disorder.
Invitae	RCV000489539	SCV001579515	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 355 of the SGSH protein (p.Glu355Lys). This variant is present in population databases (rs766938111, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of mucopolysaccharidosis type III (PMID: 11182930, 19383612, 25557439, 31718697; 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: 325835). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SGSH protein function. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000489539	SCV002045088	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000489539	SCV004030086	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: SGSH c.1063G>A (p.Glu355Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 248350 control chromosomes. c.1063G>A has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) (Beesley_2000, Sleat_2009, Nijmeijer_2019, Utz_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11182930, 31718697, 19383612, 25557439). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as pathogenic/likely pathogenic (n=5) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000489539	SCV004201072	pathogenic	Mucopolysaccharidosis, MPS-III-A	2023-10-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000489539	SCV001132285	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2018-12-07	no assertion criteria provided	clinical testing