14-87965585-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000153.4(GALC):​c.953C>G​(p.Pro318Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 17 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, 0.932
• PP5: Variant 14-87965585-G-C is Pathogenic according to our data. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965585-G-C is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 30620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.953C>G	p.Pro318Arg	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>G	p.Pro318Arg	missense_variant	Exon 9 of 17	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248926 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461280 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726966

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111614

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Pathogenic:3

Nov 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 318 of the GALC protein (p.Pro318Arg). This variant is present in population databases (rs387906954, gnomAD 0.0009%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 20886637, 27638593). This variant is also known as p.P302R. ClinVar contains an entry for this variant (Variation ID: 30620). 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 variant disrupts the p.Pro318 amino acid residue in GALC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24252386). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dec 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 31, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
PhyloP100		10
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.7	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.94
MutPred		0.72		Gain of catalytic residue at Q316 (P = 0);.;.;.;
MVP		1.0
MPC		0.60
ClinPred		0.99	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.86
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;