Submissions for variant NM_000263.4(NAGLU):c.1811C>T (p.Pro604Leu)

gnomAD frequency: 0.00002  dbSNP: rs751203469

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000670027	SCV000794837	likely pathogenic	Mucopolysaccharidosis, MPS-III-B	2017-10-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000670027	SCV001523048	pathogenic	Mucopolysaccharidosis, MPS-III-B	2019-12-06	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
CeGaT Center for Human Genetics Tuebingen	RCV001532304	SCV001747800	pathogenic	not provided	2021-03-01	criteria provided, single submitter	clinical testing
Invitae	RCV001855534	SCV002288719	likely pathogenic	Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease axonal type 2V	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 604 of the NAGLU protein (p.Pro604Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 21910976, 23100014). ClinVar contains an entry for this variant (Variation ID: 554402). 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) performed at Invitae indicates that this missense variant is expected to disrupt NAGLU protein function. Experimental studies have shown that this missense change affects NAGLU function (PMID: 29979746). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001532304	SCV002546618	pathogenic	not provided	2022-07-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on enzyme activity (Clark et al., 2018); 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: 22908982, 23100014, 21910976, 29979746)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000670027	SCV002572315	pathogenic	Mucopolysaccharidosis, MPS-III-B	2022-08-25	criteria provided, single submitter	clinical testing	Variant summary: NAGLU c.1811C>T (p.Pro604Leu) results in a non-conservative amino acid change located in the Alpha-N-acetylglucosaminidase, C-terminal domain (IPR024732) 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 1.3e-05 in 227262 control chromosomes (gnomAD). c.1811C>T has been reported in the literature in individuals affected with Mucopolysaccharidosis Type IIIB (Sanfilippo Syndrome B) (examples: Ouesleti_2011 and Klaas_2013 ). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Clark_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV000670027	SCV002578010	likely pathogenic	Mucopolysaccharidosis, MPS-III-B	2022-08-19	criteria provided, single submitter	clinical testing	ACMG categories: PM1,PM2,PP3,PP5
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000670027	SCV004807350	likely pathogenic	Mucopolysaccharidosis, MPS-III-B	2024-03-26	criteria provided, single submitter	clinical testing