ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.334A>G (p.Thr112Ala) (rs147313927)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790805 SCV000230033 uncertain significance not provided 2017-01-05 criteria provided, single submitter clinical testing
GeneDx RCV000256023 SCV000321693 uncertain significance not specified 2017-07-17 criteria provided, single submitter clinical testing The T112A variant in the GALC gene has been reported previously using alternate nomenclature (as T96A) in apatient with adult-onset Krabbe disease who harbored another possible pathogenic variant and three polymorphisms inthe GALC gene (Luzi et al., 1996). This variant has recently been reported in trans with a second suspected GALCpathogenic variant in 5 individuals across 2 generations of the same family, who all presented with late-onsetspinocerebellar ataxia and mild spasticity (Shao et al., 2016). The T112A variant was detected in more than 25% ofpatients with low GALC enzyme activity detected on newborn screening, including 8 homozygotes. However none ofthose infants received a clinical diagnosis of Krabbe disease, leading the authors to suggest that T112A may beassociated with pseudodeficiency or may be associated with late-onset Krabbe disease (Orsini et al., 2016). It has alsobeen suggested that some variants, including T112A, may only be pathogenic when present on the same allele withthe GALC polymorphism, in particular with I546T, but since these variants are seen together in the generalpopulation, the significance of the T112A variant, alone or in cis with another variant, is not clear at present (Puckettet al., 2012; communication with an external gene expert). The NHLBI Exome Sequencing Project reports T112A wasobserved in 31/8322 alleles (0.37%) from individuals of European ancestry; no individuals within this control groupwere reported as homozygous for this variant. The T112A variant is a non-conservative amino acid substitution,which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or otherproperties. This substitution occurs at a position that is conserved across species. When a construct of T112V plusthe I562T and D248N polymorphisms were expressed in COS-1 cells enzyme studies revealed the absence GALCactivity* (Luzi et al., 1996), but data on T112A alone was not reported. In summary, we interpret T112A as a variantof uncertain significance
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000178047 SCV000731413 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2017-04-14 criteria provided, single submitter clinical testing The p.Thr112Ala (NM_000153.3 c.334A>G, also referred to as p.Thr96Ala) variant i n GALC has been reported in 4 compound heterozygous individuals with clinical fe atures of late-onset Krabbe disease (Luzi 1996, Debs 2013, and Shao 2016), and s egregated in 3 affected siblings (Shao 2016). This variant is also the most comm on referral for followup testing for Krabbe disease by newborn screening program s in the heterozygous, homozygous, and compound heterozygous states (Orsini 2016 ). Upon further testing, these newborns were all classified into the moderate-, low-, or no-risk categories. This variant has been identified in 0.4% (508/12625 4) of European chromosomes and 4 homozygotes by the Genome Aggregation Database (gnomAD,; dbSNP rs147313927). This variant has also been reported in ClinVar (Variation ID#92503). In vitro functional studies provide evidence that the p.Thr112Ala variant leads to reduced enzymatic activi ty, though not at levels as low as variants causing infantile-onset disease (Saa vedra-Matiz 2016, Orsini 2016). Computational prediction tools and conservation analysis suggest that the p.Thr112Ala variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. In summary, a lthough additional studies are required to fully establish its clinical signific ance, the p.Thr112Ala variant is likely pathogenic for Krabbe disease in an auto somal recessive manner, and although at least one individual affected during chi ldhood has been reported, has typically been associated with late-onset disease. ACMG/AMP Criteria applied: PS3; PM3; PP1: PP3
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000178047 SCV000782710 uncertain significance Galactosylceramide beta-galactosidase deficiency 2017-07-24 criteria provided, single submitter clinical testing
Invitae RCV000178047 SCV000832108 uncertain significance Galactosylceramide beta-galactosidase deficiency 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 112 of the GALC protein (p.Thr112Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases, including the presence of homozygous individuals (rs147313927, ExAC 0.4%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in combination with other GALC variants in individuals affected with late-onset Krabbe disease with evidence of disease co-segregation in one family (PMID: 23197103, 26915362). This variant is also one of the most common variants that is detected in newborns who are referred for low galactocerebrosidase activity on newborn screening, but interestingly, none of the newborns were categorized as high risk for Krabbe disease (PMID: 26795590). One study has suggested that the p.Thr112Ala variant may become a disease-associated allele only when it co-occurs on the same chromosome (in cis) with the p.Ile562Thr polymorphism (PMID: 27638593). However, the evidence is not sufficient to support a pathogenic haplotype at this time. ClinVar contains an entry for this variant (Variation ID: 92503). This variant is also known as p.Thr96Ala in the literature. Experimental studies have shown that this missense change alone causes a mild reduction of GALC enzyme activity in vitro and the effect is exacerbated in the presence of other GALC variants in cis (PMID: 27638593). In summary, while this variant has been reported in individuals with Krabbe disease in the literature, it has not been found as homozygous in confirmed Krabbe disease patients and there are multiple homozyous individuals observed in population databases. In addition, clinical and experimental data suggest that co-occurrence in cis with other GALC variant(s) may be required for this variant to be disease-causing (PMID: 27638593). The available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000178047 SCV001139498 likely benign Galactosylceramide beta-galactosidase deficiency 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000790805 SCV001149290 likely pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000178047 SCV001251628 likely pathogenic Galactosylceramide beta-galactosidase deficiency 2020-02-13 criteria provided, single submitter clinical testing The GALC c.334A>G (p.Thr112Ala) variant, which was previously referred to as p.Thr96Ala, is a missense variant that has been reported in association with Krabbe disease in several studies. Shao et al. (2016) reported the variant in five members of a French-Canadian family who all presented with adult-onset disease with predominant cerebellar ataxia and mild spasticity. Nashabat et al. (2019) described a 6-year-old female with early-onset Krabbe disease who was homozygous for the p.Thr112Ala variant and showed low galactocerebrosidase enzyme activity in cultured fibroblasts but normal levels in peripheral blood. This variant was also found to be enriched among infants with GALC activity <12% of normal who were identified through newborn screening (Orsini et al. 2016) and has also been reported in a compound heterozygous state in several affected individuals who were also heterozygous for common enzyme activity-lowering variants, including p.Ile562Thr (previously p.Ile546Thr) (Luzi et al. 1996; Debs et al. 2013). Notably, this variant is reported at a frequency of 0.004022 in the European (non-Finnish) population of the Genome Aggregation Database, which also includes four homozygous carriers. Functional studies in COS1 cells showed the p.Thr112Ala-containing enzyme showed approximately 30% of wild type activity; residual activity was even lower when an additional pseudodeficiency variant was co-expressed (Luzi et al. 1996; Saavedra-Matiz et al. 2016). Marshall et al. (2018) asserted that the p.Thr112Ala variant should be considered a disease-causing allele when in cis with a common enzyme activity reducing variant or when in trans with a severe allele. Based on the collective evidence and application of the ACMG criteria, the p.Thr112Ala variant is classified as likely pathogenic for Krabbe disease.
Integrated Genetics/Laboratory Corporation of America RCV000256023 SCV001362549 uncertain significance not specified 2019-09-27 criteria provided, single submitter clinical testing Variant summary: The variant, GALC c.334A>G (p.Thr112Ala), also reported as p.Thr96Ala in the literature, results in a non-conservative amino acid change in 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 0.0025 in 248976 control chromosomes, predominantly at a frequency of 0.0041 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GALC causing Krabbe Disease phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.334A>G has been reported in the literature in multiple individuals affected with adult onset cases of Krabbe Disease (Globoid Cell Leukodystrophy (GCL); Debs _2013, Luzi _1996 ). In one French Canadian family, the variant was observed in a compound heterozygous genotype with co-segregation across two generations in 5 patients who were diagnosed with adult onset of Krabbe disease (Shao _2016). In newborn screening done for Krabbe disease at New York State, the infants carrying this variant were classified diagnostically in moderate, low, and no-risk categories, but none was classified as being at high risk (Orsini _2016). These data indicate that the variant is likely to be associated with disease with adult onset of Krabbe disease. Recently, this variant has also been reported in the literature in two homozygous individuals diagnosed with Krabbe disease (Alfares_2018, Nashabat_2019). One of these patients had infantile onset of the disease (Nashabat_2019). However, both reports do not unequivocally confirm the biochemical and clinical features of this disease either due to non-reporting of testing information in the patient reported by Alfares_2018 OR normal CSF protein levels, equivocal MRI measurements, conflicting measurements of enzyme activity in blood (normal activity) and fibroblasts (moderate reduction) and no information regarding psychosine levels in the patient reported by Nashabat_2019. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <30% of normal activity (Saavedra-Martiz_2016). In the same study, the authors also reported the presence of this variant (reported as p.T96A) in a compound heterozygous patient (among confirmed cases of Krabbe's disease) with two other severe mutations, namely p.R53X and p.R204X. This implies that p.T96A is in cis with one of these two severe mutations in this specific patient with Krabbe disease, supporting a non-pathogenic outcome for this variant. Furthermore, the authors conclude that the pathogenicity of this variant in late-onset Krabbe disease is related to its presence with a haplotype in cis with another variant, p.I546T. Five ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=4) or likely pathogenic (n=1). Based on the evidence outlined above, to reflect the variable expressivity and variable penetrance that could be associated with this variant in different genetic backgrounds, it was classified as a VUS-possibly pathogenic

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