rs749708827
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000153.4(GALC):βc.1896_1900delβ(p.Thr633AsnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,606,990 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L632L) has been classified as Likely benign.
Frequency
Consequence
NM_000153.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALC | NM_000153.4 | c.1896_1900del | p.Thr633AsnfsTer3 | frameshift_variant | 16/17 | ENST00000261304.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALC | ENST00000261304.7 | c.1896_1900del | p.Thr633AsnfsTer3 | frameshift_variant | 16/17 | 1 | NM_000153.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151952Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248814Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 135016
GnomAD4 exome AF: 0.0000254 AC: 37AN: 1455038Hom.: 0 AF XY: 0.0000235 AC XY: 17AN XY: 724350
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151952Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74210
ClinVar
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Dec 02, 2021 | This sequence change in GALC is a frameshift variant that may cause a premature stop codon, p.(Thr633Asnfs*3), that is predicted to escape nonsense mediated decay and remove <10% of the protein, however it is a truncation of a functionally important region in a gene where loss-of-function is an established disease mechanism (PMID: 27638593). This variant is present in a single individual in gnomAD v2.1 (1/112,760 alleles) in the European (non-Finnish) population. This variant has been detected in at least two individuals with Krabbe disease and deficient GALC activity. Both were compound heterozygous for the variant and a pathogenic variant and one of those were confirmed in trans by parental testing (PMID: 21824559, 22704718). RMH ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PM3, PM2_Supporting, PP4. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 04, 2023 | This variant disrupts a region of the GALC protein in which other variant(s) (p.Leu634Ser) have been determined to be pathogenic (PMID: 9272171, 16607461, 24252386, 26865610, 27679535, 27780934). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects GALC function (PMID: 27638593). This sequence change creates a premature translational stop signal (p.Thr633Asnfs*3) in the GALC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the GALC protein. This variant is present in population databases (rs749708827, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Krabbe disease (PMID: 21824559). This variant is also known as c.1848_1852del. ClinVar contains an entry for this variant (Variation ID: 555939). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 04, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 17, 2020 | Variant summary: GALC c.1896_1900delCACGT (p.Thr633AsnfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 248814 control chromosomes. c.1896_1900delCACGT has been reported in the literature in individuals affected with Krabbe Disease (Duffner_2011, Tanner_2012). These data indicate that the variant may be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated almost complete loss of activity for the truncated protein (Saavedra-Matiz_2016). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 26, 2019 | Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 53 amino acids are lost and replaced with 2 incorrect amino acids (Stenson et al., 2014; other references); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22704718, 27638593, 21824559) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at