Submissions for variant NM_000263.4(NAGLU):c.889C>T (p.Arg297Ter) (rs104894592)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000485168	SCV000330977	pathogenic	not provided	2016-06-01	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000001628	SCV000402907	pathogenic	Mucopolysaccharidosis, MPS-III-B	2017-04-28	criteria provided, single submitter	clinical testing	The NAGLU c.889C>T (p.Arg297Ter) variant is a stop-gained variant and has been reported in at least eight studies in which it is found in a total of 26 individuals with mucopolysaccharidosis, type III including three in a homozygous state, 20 in a compound heterozygous state, and three in a heterozygous state where the second allele was not identified (Zhao et al. 1996; Beesley et al. 1998; Weber et al. 1999; Yogalingham et al. 2000; Valstar et al. 2010; de Ruijter et al. 2012; Pollard et al. 2013; Welling et al. 2015). The p.Arg297Ter variant was absent from 80 control alleles but is reported at a frequency of 0.00002 in the Total population of the Exome Aggregation Consortium. Functional studies demonstrated that the variant resulted in very low levels of NAGLU enzyme activity and a 12-fold increase in glycosaminoglycan storage in individual fibroblasts compared to normal fibroblasts (Yogalingham et al. 2000). Due to the potential impact of stop-gained variants and the supporting evidence from the literature, the p.Agr297Ter variant is classified as pathogenic for mucopolysaccharidosis, type III. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000485168	SCV000568735	pathogenic	not provided	2018-11-12	criteria provided, single submitter	clinical testing	The R297X pathogenic variant in the NAGLU gene has been reported previously either in the homozygous state or in combination with another NAGLU variant in multiple unrelated individuals with MPS IIIB (Zhao et al., 1998; Yogalingam et al., 2000; Pollard et al., 2013; Meijer et al., 2016). Functional studies have shown that when R297X is expressed in CHO-K1 cells, only a truncated polypeptide that is rapidly degraded is observed, suggesting that the variant transcript undergoes nonsense-mediated mRNA decay, and no detectable enzyme activity is present (Yogalingam et al., 2000). The R297X variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R297X as a pathogenic variant.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000485168	SCV000608815	likely pathogenic	not provided	2017-05-31	criteria provided, single submitter	clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center	RCV000001628	SCV000744576	pathogenic	Mucopolysaccharidosis, MPS-III-B	2015-09-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000001628	SCV000789278	pathogenic	Mucopolysaccharidosis, MPS-III-B	2017-01-19	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000001628	SCV000919841	pathogenic	Mucopolysaccharidosis, MPS-III-B	2018-06-25	criteria provided, single submitter	clinical testing	Variant summary: NAGLU c.889C>T (p.Arg297X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position, c.1597C>T (p.Arg533X) has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 5.8e-05 in 277224 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NAGLU causing Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (5.8e-05 vs 0.0025), allowing no conclusion about variant significance. The variant, c.889C>T, has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B)(Bunge_1999, Heron_2010). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) ctie the variant as "likely pathogenic/pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000001628	SCV000021784	pathogenic	Mucopolysaccharidosis, MPS-III-B	2000-11-15	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen	RCV000001628	SCV000733578	pathogenic	Mucopolysaccharidosis, MPS-III-B		no assertion criteria provided	clinical testing