rs778447883
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000153.4(GALC):c.226G>A(p.Glu76Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000323 in 1,611,322 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E76E) has been classified as Likely benign.
Frequency
Consequence
NM_000153.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.226G>A | p.Glu76Lys | missense_variant | 2/17 | ENST00000261304.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALC | ENST00000261304.7 | c.226G>A | p.Glu76Lys | missense_variant | 2/17 | 1 | NM_000153.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 151850Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000441 AC: 11AN: 249172Hom.: 0 AF XY: 0.0000444 AC XY: 6AN XY: 135210
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1459472Hom.: 1 Cov.: 30 AF XY: 0.0000330 AC XY: 24AN XY: 726280
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 151850Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74138
ClinVar
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 30, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 29, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 76 of the GALC protein (p.Glu76Lys). This variant is present in population databases (rs778447883, gnomAD 0.009%). This missense change has been observed in individual(s) with GALC-related conditions (PMID: 26795590). This variant is also known as p.Glu60Lys. ClinVar contains an entry for this variant (Variation ID: 381334). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALC protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GALC function (PMID: 27638593). In summary, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 23, 2024 | Variant summary: GALC c.226G>A (p.Glu76Lys) results in a conservative amino acid change located in the glycosyl hydrolase family 59, catalytic domain (IPR049161) of 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 4.4e-05 in 249172 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GALC causing Krabbe Disease (4.4e-05 vs 0.0022), allowing no conclusion about variant significance. c.226G>A has been reported in the literature in 3 alleles from individuals who screened positive for Krabbe disease through a newborn screening program and were referred for confirmatory testing, although followup diagnostic testing information was only reported for one individual who was classified as low risk (Orsini_2016). This report does not provide unequivocal conclusions about association of the variant with Krabbe Disease. At least one publication reports experimental evidence evaluating an impact on protein function in vitro and found the variant results in approximately 75% of normal activity (Saavedra-Martiz_2016). The following publications have been ascertained in the context of this evaluation (PMID: 26795590, 27638593). ClinVar contains an entry for this variant (Variation ID: 381334). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 01, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in 3 alleles among 348 infants with low GALC activity detected by New York state newborn screening; however, clinical and segregation information was not provided (Orsini et al., 2016); Published functional study showed E76K, reported as E60K using alternature nomenclature, displayed only a mild reduction in enzyme activity compared to wild type (Saavedra-Matiz et al., 2016); This variant is associated with the following publications: (PMID: 26795590, 27638593) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at