rs201422931

chr14-87988206-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000153.4(GALC):c.266C>T(p.Pro89Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,613,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P89P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: GALC NM_000153.4 missense, splice_region
• Scores: Splicing: ADA: 0.9785
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9
• Conservation: PhyloP100: 7.42

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.266C>T	p.Pro89Leu	missense_variant, splice_region_variant	3/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.266C>T	p.Pro89Leu	missense_variant, splice_region_variant	3/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152036 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000144 AC: 36 AN: 249270 Hom.: 0 AF XY: 0.000148 AC XY: 20 AN XY: 135270

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.000169 AC: 247 AN: 1461012 Hom.: 0 Cov.: 31 AF XY: 0.000166 AC XY: 121 AN XY: 726836

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000180

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152036 Hom.: 0 Cov.: 33 AF XY: 0.0000808 AC XY: 6 AN XY: 74270

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000245 AC: 2

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2017	The P89L variant in the GALC gene has been reported previously in several infants with low GALC activity on newborn screening, including at least one individual who was found to have a partial gene deletion on the oppositive GALC allele (in trans) (Orsini et al., 2016). The P89L variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The P89L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies demonstrate that the P89L variant is associated with decreased enzyme activity (Saavedra-Matiz et al., 2016). We interpret P89L as a pathogenic variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	GALC: PM2, PP3, PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 21, 2023	PP3, PM2, PM3_supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2017	- -

Galactosylceramide beta-galactosidase deficiency Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	Mar 14, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 07, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 89 of the GALC protein (p.Pro89Leu). This variant is present in population databases (rs201422931, gnomAD 0.03%). This missense change has been observed in individual(s) with low GALC enzyme activity (PMID: 26795590). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.P73L. ClinVar contains an entry for this variant (Variation ID: 449966). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GALC function (PMID: 27638593). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 11, 2024

Variant summary: GALC c.266C>T (p.Pro89Leu) 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 0.00014 in 249270 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GALC causing Krabbe Disease (0.00014 vs 0.0022), allowing no conclusion about variant significance. c.266C>T has been reported in the literature in an infant with low GALC enzyme activity during newborn screening who carried a large deletion on the second allele (Orsini_2016). These data do not allow any conclusion about variant significance. The variant was reported to lead to around 20% residual GALC activity in an in vitro study (Saavedra-Martin_2016). The following publications have been ascertained in the context of this evaluation (PMID: 26795590, 27638593). ClinVar contains an entry for this variant (Variation ID: 449966). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Mar 18, 2019

ACMG classification criteria: PM1, PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-9.6	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.88
MVP		0.98
MPC		0.58
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.88
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.84
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

Publications

LitVar

Other links and lift over

dbSNP: rs201422931; hg19: chr14-88454550; COSMIC: COSV54331416; COSMIC: COSV54331416;