Submissions for variant NM_000263.4(NAGLU):c.419A>G (p.Tyr140Cys) (rs753520553)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409594	SCV000487266	pathogenic	Mucopolysaccharidosis, MPS-III-B	2016-11-04	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000626636	SCV000747338	pathogenic	Hypertrichosis; Abnormality of metabolism/homeostasis; Coarse facial features; Abnormal facial shape; Thick eyebrow; Hepatosplenomegaly; Mucopolysacchariduria; Intellectual disability, severe	2017-01-01	criteria provided, single submitter	clinical testing
Invitae	RCV000705481	SCV000834480	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V	2019-03-21	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with cysteine at codon 140 of the NAGLU protein (p.Tyr140Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs753520553, ExAC 0.009%). This variant has been reported to co-occur with different NAGLU variants or as homozygous in multiple individuals affected with mucopolysaccharidosis IIIB (PMID: 9950362, 9443875, 26907177, 9443878, 11153910). It has also been reported in families with evidence of co-segregation with disease (PMID: 14984474). ClinVar contains an entry for this variant (Variation ID: 371634). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America	RCV000409594	SCV000919842	pathogenic	Mucopolysaccharidosis, MPS-III-B	2018-07-06	criteria provided, single submitter	clinical testing	Variant summary: NAGLU c.419A>G (p.Tyr140Cys) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, tim-barrel domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 246256 control chromosomes (gnomAD). The variant, c.419A>G, has been reported in the literature in multiple compound heterozygote and homozygote individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B)(Beesley_1998, Bunge_1998, Meijer_2016, Tessitore_2000). These data indicate that the variant is very likely to be associated with disease. The affected patients were found to have significantly decreased enzyme activity (<10%)(Beesley_1998). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Diagnosis and Therapy of Lysosomal Disorders,University of Padova	RCV000409594	SCV000929906	likely pathogenic	Mucopolysaccharidosis, MPS-III-B	2019-01-01	criteria provided, single submitter	literature only	PS3: Low in vitro enzymatic activity. PM2: Very low frequency in ExAC

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