ClinVar Miner

Submissions for variant NM_000199.5(SGSH):c.673T>C (p.Phe225Leu) (rs1057521801)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Geisinger Autism and Developmental Medicine Institute,Geisinger Health System RCV000489872 SCV000575936 pathogenic Mucopolysaccharidosis, MPS-III-A 2017-04-26 criteria provided, single submitter clinical testing The following ACMG criteria are met: PS1 (Same amino acid change as pathogenic variant, Heron 2010), PS3 (Well-established functional study), PM2 (Absent from population databases), PM3 (In trans with pathogenic variant), PP1 (Co-segregation with disease in multiple family members). Two sisters in our clinical practice are compound heterozygotes for E355K and P225L and a clinical diagnosis of MPS IIIA was confirmed by clinical exam, positive urine screen, and absent enzyme activity in leukocytes. The younger sister has global developmental delays, autism spectrum disorder, sensorineural hearing loss, myopia, astigmatism, and a seizure disorder. The older sister has intellectual disability, autism spectrum disorder, sensorineural hearing loss, myopia, astigmatism, recurrent otitis media, precocious puberty, and seizure disorder.
GeneDx RCV000426187 SCV000524593 likely pathogenic not provided 2016-10-31 criteria provided, single submitter clinical testing The c.673 T>C nucleotide substitution, resulting in the F225L amino acid change, has not been reported previously as a pathogenic or benign variant to our knowledge. However, a different nucleotide substitution (c.675C>G) that also results in the F225L missense substitution was previously identified in two families with mucopolysaccharidosis type IIIA (MPSIIIA), supporting the functional importance of this position in the protein (Heron et al., 2010). Additionally, a missense variant in a neighboring codon (P227R) has been reported in the Human Gene Mutation Database in association with MPSIIIA (Stenson et al., 2014). The F225L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The F225L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.

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