Submissions for variant NM_000263.4(NAGLU):c.934G>A (p.Asp312Asn)

gnomAD frequency: 0.00001  dbSNP: rs1052471595

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000501703	SCV000590927	pathogenic	Mucopolysaccharidosis, MPS-III-B	2018-08-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624490	SCV000741285	likely pathogenic	Inborn genetic diseases	2017-03-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000501703	SCV001140447	likely pathogenic	Mucopolysaccharidosis, MPS-III-B	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV001591146	SCV001822647	pathogenic	not provided	2024-10-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 25525159, 28844463, 21204211, 34426522, 34396902, 32883051, 31969655, 29269699, 33747789)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000501703	SCV002051131	pathogenic	Mucopolysaccharidosis, MPS-III-B	2021-12-15	criteria provided, single submitter	clinical testing	Variant summary: NAGLU c.934G>A (p.Asp312Asn) results in a conservative amino acid change located in the Alpha-N-acetylglucosaminidase, tim-barrel domain (IPR024733) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251390 control chromosomes. c.934G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (example, Heron_2010, Yassaee_2017, Ozkinay_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Although some patients ascertained above were reported as having decreased alpha-N-acetylglucosaminidase enzyme activity without presenting the primary data (example, Ozkinay_2021). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/Likely Pathogenic, n=4; VUS, n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865629	SCV002118348	pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 312 of the NAGLU protein (p.Asp312Asn). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with Mucopolysaccharidosis type III and/or NAGLU-related conditions (PMID: 21204211, 28844463, 29269699, 31969655, 32883051, 33747789, 34396902). ClinVar contains an entry for this variant (Variation ID: 437446). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NAGLU protein function. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000501703	SCV000794338	uncertain significance	Mucopolysaccharidosis, MPS-III-B	2017-09-24	flagged submission	clinical testing
New York Genome Center	RCV000501703	SCV001622888	uncertain significance	Mucopolysaccharidosis, MPS-III-B	2020-05-07	flagged submission	clinical testing
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319203	SCV004023193	likely pathogenic	Tip-toe gait	2022-12-14	no assertion criteria provided	clinical testing	Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.