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

dbSNP: rs1057521801

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
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.
Genome-Nilou Lab	RCV000489872	SCV002045498	pathogenic	Mucopolysaccharidosis, MPS-III-A	2021-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV000489872	SCV003322257	likely pathogenic	Mucopolysaccharidosis, MPS-III-A	2022-02-24	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 21204211). 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. 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 SGSH protein function. ClinVar contains an entry for this variant (Variation ID: 383967). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 225 of the SGSH protein (p.Phe225Leu).