ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD, LLC RCV000413635 SCV000203561 pathogenic not provided 2018-08-17 criteria provided, single submitter clinical testing
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.
GeneDx RCV000413635 SCV000491269 pathogenic not provided 2021-11-09 criteria provided, single submitter clinical testing 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)
Ambry Genetics RCV000624626 SCV000741896 pathogenic Inborn genetic diseases 2016-11-23 criteria provided, single submitter clinical testing
Invitae RCV000005421 SCV000815696 pathogenic Mucopolysaccharidosis, MPS-III-A 2020-10-20 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
Baylor Genetics RCV000005421 SCV001520414 pathogenic Mucopolysaccharidosis, MPS-III-A 2019-07-03 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Nilou-Genome Lab RCV000005421 SCV002045480 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2021-11-07 criteria provided, single submitter clinical testing
OMIM RCV000005421 SCV000025603 pathogenic Mucopolysaccharidosis, MPS-III-A 1997-05-01 no assertion criteria provided literature only
Counsyl RCV000005421 SCV000800766 likely pathogenic Mucopolysaccharidosis, MPS-III-A 2017-05-24 no assertion criteria provided clinical testing

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