rs111033717

Positions:

• chr9-34648159-C-A
• chr9-34648159-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000155.4(GALT):​c.552C>A​(p.His184Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,844 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H184D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: -0.0420

Genes affected

GALT (HGNC:4135): (galactose-1-phosphate uridylyltransferase) Galactose-1-phosphate uridyl transferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely the conversion of UDP-glucose + galactose-1-phosphate to glucose-1-phosphate + UDP-galactose. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000155.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-34648157-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2735269.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 9-34648159-C-A is Pathogenic according to our data. Variant chr9-34648159-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 25210.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALT	NM_000155.4	c.552C>A	p.His184Gln	missense_variant	6/11	ENST00000378842.8
GALT	NM_001258332.2	c.225C>A	p.His75Gln	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000378842.8	c.552C>A	p.His184Gln	missense_variant	6/11	1	NM_000155.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461844 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 184 of the GALT protein (p.His184Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with classic galactosemia (PMID: 10535394, 11397328). ClinVar contains an entry for this variant (Variation ID: 25210). 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 GALT protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 09, 2022	Variant summary: GALT c.552C>A (p.His184Gln) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, N-terminal domain (IPR005849) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251476 control chromosomes. c.552C>A has been reported in the literature in individuals affected with Galactosemia (example, Palmieri_1999, Yang_2002, Berry_2004, Robertson_2000). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic/Likely Pathogenic, n=3; VUS, n=1). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 22, 2024	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 07, 2016	The H184Q variant in the GALT gene has been reported previously in patients with galactosemia (Tyfield et al. 1999; Yang et al. 2002). The H184Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H184Q variant is a semi-conservative amino acid substitution. The H184Q variant occurs at a position within the catalytic site of the galactose 1-phosphate uridyltransferase protein that is conserved across species (Elsas et al. 1998). In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret H184Q as being likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 29, 2023	PP3, PP4, PM2, PM3_strong, PS4_moderate -

Galactosemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 14, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.98	.;D;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.9	.;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-8.0	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;T
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.98
MutPred		0.98		.;Loss of disorder (P = 0.1762);.;
MVP		0.95
MPC		1.9
ClinPred		1.0	D
GERP RS		-5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs111033717; hg19: chr9-34648156;