ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.1949T>C (p.Leu650Pro) (rs1249991480)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671889 SCV000796920 uncertain significance Galactosylceramide beta-galactosidase deficiency 2018-01-08 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000995226 SCV001149289 uncertain significance not provided 2016-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420862 SCV001623279 uncertain significance not specified 2021-05-15 criteria provided, single submitter clinical testing Variant summary: GALC c.1949T>C (p.Leu650Pro) (legacy name p.Leu634Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247910 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1949T>C has always been reported in the literature as a complex allele in combination with another variant, p.Ile562Thr (legacy name p.Ile546Thr) in settings of newborn screening for Krabbe's disease and in compound heterozygosity with another complex allele combination in at-least one individual affected with Krabbe Disease (example, Saavendra-Matiz_2016, Bascou_2018). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Krabbe Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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