rs200607029
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2
The NM_000153.4(GALC):c.2041G>A(p.Val681Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,613,206 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000075 ( 2 hom. )
Consequence
GALC
NM_000153.4 missense
NM_000153.4 missense
Scores
7
7
5
Clinical Significance
Conservation
PhyloP100: 1.53
Genes affected
GALC (HGNC:4115): (galactosylceramidase) This gene encodes a lysosomal protein which hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Mutations in this gene have been associated with Krabbe disease, also known as globoid cell leukodystrophy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP5
Variant 14-87934749-C-T is Pathogenic according to our data. Variant chr14-87934749-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208291.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=2, Likely_pathogenic=4}.
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.2041G>A | p.Val681Met | missense_variant | 17/17 | ENST00000261304.7 | NP_000144.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152046Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000193 AC: 48AN: 248920Hom.: 0 AF XY: 0.000170 AC XY: 23AN XY: 135046
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GnomAD4 exome AF: 0.0000753 AC: 110AN: 1461042Hom.: 2 Cov.: 31 AF XY: 0.0000798 AC XY: 58AN XY: 726842
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GnomAD4 genome AF: 0.0000723 AC: 11AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74404
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Pathogenic:5Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 24, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Uncertain significance, no assertion criteria provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | Jun 27, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 29, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 681 of the GALC protein (p.Val681Met). This variant is present in population databases (rs200607029, gnomAD 0.1%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 23462331, 31885218). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208291). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 16, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 11, 2023 | The significance of this variant, alone or in cis with another variant is not clear at present (PMID: 27638593); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(V665M); This variant is associated with the following publications: (PMID: 34426522, 31589614, 36161165, 36341094, 23462331, 31885218, 35419325, 27638593) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2023 | Variant summary: GALC c.2041G>A (p.Val681Met) results in a 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 0.00019 in 248920 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GALC causing Krabbe Disease (0.00019 vs 0.0022), allowing no conclusion about variant significance. c.2041G>A has been reported in the literature as a compound heterozygous genotype in two individuals affected with adult onset presentations of Krabbe Disease (example, Yang_2013, Xie_2020) and one case of Krabbe Diasese diagnosed at newborn screening (Li_2022). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Saavendra-Matiz_2016). These results showed no damaging effect of this variant in isolation but when associated in cis with a different variant, namely p.I546T, a "haplotype effect" was observed such that the construct bearing p.V665M+p.I546T in cis demonstrated GALC enzyme activity of approximately 30% of normal WT levels. This variant is characterized as a mild allele when in cis with p.I546T. Lastly, the presence of this co-occurring allele in the three ascertained cases mentioned above cannot be unequivocally ruled out. The following publications have been ascertained in the context of this evaluation (PMID: 35419325, 27638593, 31885218, 23462331). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=4) and VUS (n=1). Based on the evidence outlined above, the variant in isolation was classified as VUS-possibly pathogenic. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 01, 2024 | The c.2041G>A (p.V681M) alteration is located in exon 17 (coding exon 17) of the GALC gene. This alteration results from a G to A substitution at nucleotide position 2041, causing the valine (V) at amino acid position 681 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;.
Vest4
MutPred
Loss of sheet (P = 0.0037);.;.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at