ClinVar Miner

Submissions for variant NM_000153.4(GALC):c.136G>T (p.Asp46Tyr) (rs751975987)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781395 SCV000919391 pathogenic Galactosylceramide beta-galactosidase deficiency 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The GALC c.136G>T (p.Asp46Tyr) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 9/149232 control chromosomes at a frequency of 0.0000603, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALC variant (0.0022361). The variant was reported in several patients in compound heterozygosity with at least two likely pathogenic/pathogenic mutations and biochemical findings suggestive of Krabbe disease (Pchelina_2014; Zhao_2017). Per latest published reports, c.136G>T is associated with a mild clinical course of disease (Zhao_2017). Taken together, this variant is classified as Pathogenic.
Invitae RCV000781395 SCV000946629 pathogenic Galactosylceramide beta-galactosidase deficiency 2020-04-06 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 46 of the GALC protein (p.Asp46Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs751975987, ExAC 0.2%). This variant has been observed in individual(s) with Krabbe disease (PMID: 31185936, 24078576, 28598007, external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 633229). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.

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