chr14-87965585-G-A

Variant names:

• chr14-87965585-G-A
• rs387906954
• NM_000153.4:c.953C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_000153.4(GALC):​c.953C>T​(p.Pro318Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P318A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.96
• Publications: 10 publications found

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]

GALC Gene-Disease associations (from GenCC):

• Krabbe disease

  Inheritance: 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

LOC124903355 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000153.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-87965586-G-C is described in CliVar as Pathogenic. Clinvar id is 370631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.18582 (below the threshold of 3.09). Trascript score misZ: -0.28853 (below the threshold of 3.09). GenCC associations: The gene is linked to Krabbe disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914
• PP5: Variant 14-87965585-G-A is Pathogenic according to our data. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-87965585-G-A is described in CliVar as Likely_pathogenic. Clinvar id is 2579652.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.953C>T	p.Pro318Leu	missense_variant	Exon 9 of 17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.953C>T	p.Pro318Leu	missense_variant	Exon 9 of 17	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Pathogenic:1 Other:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 318 of the GALC protein (p.Pro318Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Krabbe disease (PMID: 28598007). This variant disrupts the p.Pro318 amino acid residue in GALC. Other variant(s) that disrupt this residue have been observed in individuals with GALC-related conditions (PMID: 20886637, 24252386, 27638593, 29615819), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
PhyloP100		10
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.5	D;D;D;D
REVEL	Pathogenic	0.80
Sift	Benign	0.067	T;D;T;D
Sift4G	Uncertain	0.056	T;D;D;T
Polyphen		0.96	D;D;P;.
Vest4		0.83
MutPred		0.70		Gain of catalytic residue at Q316 (P = 0);.;.;.;
MVP		0.99
MPC		0.58
ClinPred		1.0	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.84
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs387906954; hg19: chr14-88431929;