ClinVar Miner

Submissions for variant NM_000263.4(NAGLU):c.1946G>T (p.Trp649Leu) (rs527236038)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001378699 SCV001576325 likely pathogenic Mucopolysaccharidosis, MPS-III-B; Charcot-Marie-Tooth disease, axonal type 2V 2020-01-29 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with leucine at codon 649 of the NAGLU protein (p.Trp649Leu). The tryptophan residue is highly conserved and there is a small physicochemical difference between tryptophan and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 23661660). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 143187). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). This variant disrupts the p.Trp649 amino acid residue in NAGLU. Other variant(s) that disrupt this residue have been observed in individuals with NAGLU-related conditions (PMID: 11153910), which suggests that this may be a clinically significant amino acid residue. 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.
Undiagnosed Diseases Program Translational Research Laboratory,National Institutes of Health RCV000132721 SCV000187650 pathogenic Mucopolysaccharidosis, MPS-III-B no assertion criteria provided not provided Converted during submission to Pathogenic.

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