ClinVar Miner

Submissions for variant NM_000404.4(GLB1):c.602G>A (p.Arg201His) (rs189115557)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665698 SCV000789861 likely pathogenic GM1 gangliosidosis type 2; Gangliosidosis GM1 type 3; Mucopolysaccharidosis, MPS-IV-B; Infantile GM1 gangliosidosis 2017-02-23 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000255006 SCV000231531 pathogenic not provided 2014-10-27 criteria provided, single submitter clinical testing
GeneDx RCV000255006 SCV000321731 pathogenic not provided 2018-05-02 criteria provided, single submitter clinical testing The R201H variant has previously been associated with both juvenile and adult-onset GM1-gangliosidosis as well as with Morquio B disease (Hofer et al., 2009; Santamaria et al. 2007). The R201H variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R201H variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies showed that R201H was associated with a decreased amount of enzyme function (Hofer et al., 2009; Santamaria et al. 2007). We interpret R201H as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000309607 SCV000443184 pathogenic GM1 gangliosidosis 2017-04-27 criteria provided, single submitter clinical testing The GLB1 c.602G>A (p.Arg201His) missense variant has been identified in a compound heterozygous state with an additional missense variant in eight individuals with GM1 gangliosidosis (Kaye et al. 1997; Morrone et al. 2000; Paschke et al. 2001; Caciotti et al. 2005; Santamaria et al. 2006; Hofer et al. 2009; Pierson et al. 2012). The p.Arg201His variant has also been reported in a compound heterozygous state in combination with another missense variant in two individuals with an intermediate phenotype between mucopolysaccharidosis (MPS) type IVB and the adult form of GM1 gangliosidosis (Hofer et al. 2009; Moore et al. 2013) and in a homozygous state in an individual with MPS type IVB (Santamaria et al. 2006). The Arg201 residue is highly conserved across vertebrate species (Pierson et al. 2012), and was shown to segregate with disease in an autosomal recessive inheritance pattern where family data were available (Morrone et al. 2000; Paschke et al. 2001; Pierson et al. 2012). The p.Arg201His variant was absent from 140 controls (Kaye et al. 1997; Paschke et al. 2001) and is reported at a frequency of 0.00011 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in individual leukocytes and fibroblasts carrying the p.Arg201His variant demonstrated a significant reduction in enzyme activity to between 2% and 2.5% of wildtype (Kaye et al. 1997; Caciotti et al. 2005). Based on the collective evidence, the p.Arg201His variant is classified as pathogenic for GLB1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000818052 SCV000958646 pathogenic Mucopolysaccharidosis, MPS-IV-B; GM1 gangliosidosis 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 201 of the GLB1 protein (p.Arg201His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs189115557, ExAC 0.01%). This variant has been observed in several individuals and families affected with GM1 gangliosidosis and Morquio B disease (PMID: 9203065, 11511921, 17309651, 20175788, 23430499). ClinVar contains an entry for this variant (Variation ID: 198077). Experimental studies have shown that this missense change has a deleterious effect on protein function (PMID: 9203065, 17664528, 16617000, 11504597). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000309607 SCV000966893 pathogenic GM1 gangliosidosis 2018-09-19 criteria provided, single submitter clinical testing The p.Arg201His variant in GLB1 has been reported in at least 10 individuals wit h clinical features of GM1 gangliosidosis type II/III or Mucopolysaccharidosis t ype IV (Morquio syndrome), all of whom were homozygous or compound heterozygous, and segregated with the disease in 1 affected family member (Kaye 1997, Morrone 2000, Santamaria 2006, Santamaria 2007, Hofer 2009, Pierson 2012). This variant has been reported in ClinVar (Variation ID# 198077) and was absent from large p opulation studies. In vitro functional studies provide some evidence that the p. Arg201His variant may impact protein function (Kaye 1997, Iwasaki 2006, Santamar ia 2007). In summary, this variant meets criteria to be classified as pathogenic for GLB1-related disorders in an autosomal recessive manner based upon case obs ervation, segregation studies, absence from controls and functional evidence. AC MG/AMP Criteria applied: PM3_VeryStrong, PM2, PS3_Moderate, PP1

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