ClinVar Miner

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

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Total submissions: 5
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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, http://gnomad.broadinstitute.org/; 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 2018-12-26 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 (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 Krabbe disease with evidence of disease co-segregation in one family (PMID: 23197103, 26915362). However, data in the literature also indicate that only when the p.Thr112Ala variant co-occurs on the same chromosome (in cis) with the p.Ile562Thr polymorphism does it become a disease-causing allele (PMID: 27638593, 26795590).  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.

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