14-87965582-T-C
Variant summary
Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBS1_SupportingBS2
The NM_000153.4(GALC):c.956A>G(p.Tyr319Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00079 in 1,613,458 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y319Y) has been classified as Likely benign.
Frequency
Consequence
NM_000153.4 missense
Scores
Clinical Significance
Conservation
Publications
- Krabbe diseaseInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp
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ACMG classification
Our verdict: Likely_benign. The variant received -6 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| GALC | NM_000153.4 | c.956A>G | p.Tyr319Cys | missense_variant | Exon 9 of 17 | ENST00000261304.7 | NP_000144.2 |
Ensembl
Frequencies
GnomAD3 genomes 0.000454 AC: 69AN: 152072Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00149 AC: 371AN: 248972 AF XY: 0.00190 show subpopulations
GnomAD4 exome AF: 0.000827 AC: 1208AN: 1461268Hom.: 14 Cov.: 32 AF XY: 0.00111 AC XY: 807AN XY: 726952 show subpopulations
Age Distribution
GnomAD4 genome 0.000440 AC: 67AN: 152190Hom.: 0 Cov.: 33 AF XY: 0.000551 AC XY: 41AN XY: 74410 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Galactosylceramide beta-galactosidase deficiency Pathogenic:7Uncertain:4Benign:1
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Krabbe disease (MIM#245200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Disease severity and age of onset can be highly variable even within families (OMIM; PMID: 33178108) (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (368 heterozygotes, 3 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 59 (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals and is also known as p.(Tyr303Cys) due to alternate nomenclature. The variant has previously been described as pathogenic in multiple individuals with Krabbe disease and is considered to be a hypomorphic allele which results in disease when in trans with a more severe variant (PMIDs: 10234611, 22115770, 22520351, 23197103, 24388568, 26795590, 27638593, 29481565, 30089515, 31093932). However, this variant has also been reported in at least three homozygous patients with juvenile and late-infantile onset phenotype (PMID: 33178108). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Studies have demonstrated significantly reduced GALC activity in patients, and functional work in transfected cells showed that the variant results in ER retention and is therefore not properly trafficked to lysosomes, likely due to protein misfolding (PMIDs: 10234611, 22520351, 27126738, 30089515). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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The Y319C variant (reported as Y303C due to the use of alternate nomenclature) has been published previously in multiple unrelated individuals with later-onset Krabbe disease and absent or significantly reduced galactocerebrosidase enzyme activity who harbored a second pathogenic variant on the other allele (Debs et al, 2013; Duffner et al, 2012; Farina et al, 2000).In vitro functional studies showed a significant decrease in enzyme activity (Saavedra-Matiz CA et al). The variant has been submitted to ClinVar as Pathogenic. The Y319C variant was observed on 1% alleles from individuals of South Asian background in the Exome Aggregation Consortium (ExAC) data set.In silico analysis predicts the variant to be damaging and the residue is moderately conserved across species. Based on the above the variant is classified as Pathogenic. -
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
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This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 319 of the GALC protein (p.Tyr319Cys). This variant is present in population databases (rs183105855, gnomAD 1.0%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of Krabbe disease (PMID: 11003282, 22520351, 23197103, 27535533). This variant is also known as p.Y303C. ClinVar contains an entry for this variant (Variation ID: 265349). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GALC protein function. 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. -
The heterozygous p.Tyr319Cys variant in GALC has been identified in an individual in the compound heterozygous state with 20% of normal GALC enzyme activitiy and Krabbe disease (PMID: 22520351), and has been identified in >1% of South Asian chromosomes and 2 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive Krabbe disease. -
not provided Pathogenic:2Uncertain:2Benign:1
GALC: BS2 -
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DNA sequence analysis of the GALC gene demonstrated a sequence change, c.956A>G, in exon 9 that results in an amino acid change, p.Tyr319Cys. This sequence change has been described in the gnomAD database with a population frequency of 0.13% (dbSNP rs183105855). This is a common pathogenic sequence change that has previously been described in multiple patients with later-onset Krabbe disease in the homozygous and compound heterozygous states. These patients had absent or significantly reduced galactocerebrosidase activity (PMIDs: 22520351, 22115770). Experimental studies have demonstrated that this variant disrupts protein trafficking likely due to protein misfolding (PMID: 27126738). The p.Tyr319Cys change affects a moderately conserved amino acid residue located in a domain of the GALC protein that is known to be functional. The p.Tyr319Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Mutation Taster, REVEL). These collective evidences indicate that this sequence change is pathogenic. -
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One of the most common variants observed in individuals identified by newborn screening, where it typically observed on the same allele (in cis) with the p.(D248N) variant; these individuals have not developed Krabbe disease in childhood, but some individuals had psychosine in the intermediate range (PMID: 26795590, 34065072, 33832819); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27126738, 27535533, 27638593, 22520351, 34426522, 23197103, 11003282, 33832819, 35002157, 34670123, 31069529, 35460079, 36920572, 36964972, 37432431, 34065072, 26795590, 38532509, 33178108, 40542290) -
not specified Pathogenic:1Uncertain:1Benign:1
Variant summary: GALC c.956A>G (p.Tyr319Cys) also reported as p.Tyr303Cys in literature 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 0.0015 in 248972 control chromosomes in the gnomAD database, including 3 homozygotes. In particular, it is relatively more commonly found in South Asian subpopulation at a frequency of 0.0097. The overall frequency is not significantly higher than expected for a pathogenic variant in GALC causing Krabbe Disease, allowing no conclusion about variant significance. c.956A>G has been reported in the literature as presumably compound heterozygous genotype in a series of adults with Krabbe Disease (Debs_2012) and/or without phase specification with another pathogenic GALC variant in an individual with later onset Krabbe Disease (Duffner_2012). Other studies report that none of the infants homozygous or compound heterozygous for p.Y303C is known to have been diagnosed with Krabbe Disease (Orsini_2016). These studies do not provide unequivocal conclusions about the association of this variant with Krabbe Disease. At-least two publications report experimental evidence evaluating an impact on protein function, however, do not allow convincing conclusions about the variant effect in isolation (example, Saavendra-Martiz_2016, Duffner_2012). The following publications have been ascertained in the context of this evaluation (PMID: 23197103, 22520351, 26795590, 27638593). ClinVar contains an entry for this variant (Variation ID: 265349). Based on the evidence outlined above, the variant was classified as uncertain significance. -
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GALC-related disorder Uncertain:1
The GALC c.956A>G variant is predicted to result in the amino acid substitution p.Tyr319Cys. This variant has been reported in compound heterozygous states with other potentially pathogenic GALC variants (missense variant and 30-kb gross deletion) in multiple unrelated patients with late-onset Krabbe disease who had reduced enzyme activity (Duffner et al., 2012. PubMed ID: 22520351; Farina et al., 2000. PubMed ID: 11003282). Results obtained from in-vitro studies suggested that the p.Tyr319Cys variant is likely to cause disease due to protein misfolding (Spratley et al., 2016. PubMed ID: 27126738). This variant is reported in 0.97% of alleles in individuals of South Asian descent in gnomAD, including three homozygous individuals (http://gnomad.broadinstitute.org/variant/14-88431926-T-C). However, to date there is no known case of Krabbe disease with homozygous p.Tyr319Cys variant (www.mdpi.com/2409-515X/3/1/3/pdf). This variant has conflicting interpretations of pathogenicity in ClinVar ranging from benign to pathogenic (http://www.ncbi.nlm.nih.gov/clinvar/variation/265349). Although we suspect that this variant may be pathogenic, at this time its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at