ClinVar Miner

Submissions for variant NM_000199.3(SGSH):c.1063G>A (p.Glu355Lys) (rs766938111)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
GeneDx RCV000414288 SCV000491270 likely pathogenic not provided 2016-03-03 criteria provided, single submitter clinical testing The E355K variant in the SGSH gene has been reported previously in association with autosomal recessive mucopolysaccharidosis type IIIA when present in trans with another disease-causing pathogenic variant (Beesley et al., 2000; Kousi et al., 2012). Structural analysis of SGSH using a crystal model predicted the E355K variant resulted in the loss of the surface salt bridge with Arg304 and of the hydrogen bonds to Ser309 and Glu310 (Sidhu et al., 2014). The E355K variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E355K variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The E355K variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Illumina Clinical Services Laboratory,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.

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