ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.1339G>A (p.Glu447Lys) (rs104894639)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000624626 SCV000741896 pathogenic Inborn genetic diseases 2016-11-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Counsyl RCV000005421 SCV000800766 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2017-05-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000413635 SCV000203561 pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing
GeneDx RCV000413635 SCV000491269 likely pathogenic not provided 2016-03-21 criteria provided, single submitter clinical testing The E447K variant in the SGSH gene has been previously reported in association with MPS Type IIIA (Blanch et al., 1997; Chabas et al., 2001; Matalonga et al., 2014). This 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 E447K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The E447K 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 RCV000005421 SCV000407341 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2017-04-27 criteria provided, single submitter clinical testing 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.
Invitae RCV000005421 SCV000815696 pathogenic Mucopolysaccharidosis, MPS-III-A 2018-09-14 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 447 of the SGSH protein (p.Glu447Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs104894639, ExAC 0.009%). This variant has been observed as homozygous or in combination with other SGSH variants in individuals affected with mucopolysaccharidosis (MPS) type IIIA (PMID: 9158154, 26787381, 19099774). In addition, this variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with MPS IIIA (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease.  ClinVar contains an entry for this variant (Variation ID: 5114). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova RCV000005421 SCV000929903 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2019-01-01 criteria provided, single submitter literature only PS3: Low in vivo enzymatic activity in homozygotes; PM2: Very low frequency in GnomAD
OMIM RCV000005421 SCV000025603 pathogenic Mucopolysaccharidosis, MPS-III-A 1997-05-01 no assertion criteria provided literature only

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