Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
EGL Genetic Diagnostics, |
RCV000485168 | SCV000330977 | pathogenic | not provided | 2016-06-01 | criteria provided, single submitter | clinical testing | |
Illumina Clinical Services Laboratory, |
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. |
Gene |
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. |
Ce |
RCV000485168 | SCV000608815 | likely pathogenic | not provided | 2019-09-01 | criteria provided, single submitter | clinical testing | |
DNA and Cytogenetics Diagnostics Unit, |
RCV000001628 | SCV000744576 | pathogenic | Mucopolysaccharidosis, MPS-III-B | 2015-09-21 | 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. |
Invitae | RCV001041784 | SCV001205422 | pathogenic | Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V | 2019-10-11 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg297*) in the NAGLU gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs104894592, ExAC 0.01%). This variant has been observed to be homozygous or in combination with another NAGLU variant in several individuals affected with mucopolysaccharidosis type III (PMID: 28836185, 22976768). ClinVar contains an entry for this variant (Variation ID: 1562). Loss-of-function variants in NAGLU are known to be pathogenic (PMID: 9832037, 10094189, 16151907). For these reasons, this variant has been classified as Pathogenic. |
OMIM | RCV000001628 | SCV000021784 | pathogenic | Mucopolysaccharidosis, MPS-III-B | 2000-11-15 | no assertion criteria provided | literature only | |
Diagnostic Laboratory, |
RCV000001628 | SCV000733578 | pathogenic | Mucopolysaccharidosis, MPS-III-B | no assertion criteria provided | clinical testing | ||
Counsyl | RCV000001628 | SCV000789278 | pathogenic | Mucopolysaccharidosis, MPS-III-B | 2017-01-19 | no assertion criteria provided | clinical testing | |
Gene |
RCV001030805 | SCV001194294 | pathogenic | Mucopolysaccharidosis | 2019-09-04 | no assertion criteria provided | literature only | |
Natera, |
RCV000001628 | SCV001463385 | pathogenic | Mucopolysaccharidosis, MPS-III-B | 2020-09-16 | no assertion criteria provided | clinical testing |