rs111033754

Positions:

chr9-34648766-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000155.4(GALT):c.692G>A(p.Arg231His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,162 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GALT
NM_000155.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.31

Variant links:

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]

GALT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 9-34648766-G-A is Pathogenic according to our data. Variant chr9-34648766-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALT	NM_000155.4 linkuse as main transcript	c.692G>A	p.Arg231His	missense_variant	8/11	ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2 linkuse as main transcript	c.365G>A	p.Arg122His	missense_variant	6/9		NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8 linkuse as main transcript	c.692G>A	p.Arg231His	missense_variant	8/11	1	NM_000155.4	ENSP00000368119	P1	P07902-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250550

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135492

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461034

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726888

show subpopulations

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 03, 2021	NM_000155.3(GALT):c.692G>A(R231H) is a missense variant classified as likely pathogenic in the context of galactosemia. R231H has been observed in cases with relevant disease (PMID: 7550229, 22944367, 23924834, 27176039). Functional assessments of this variant are available in the literature (PMID: 11152465, 25614870). R231H has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, NM_000155.3(GALT):c.692G>A(R231H) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 23, 2021	Variant summary: GALT c.692G>A (p.Arg231His) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, C-terminal domain (IPR005850) of 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 4e-06 in 250550 control chromosomes (gnomAD). c.692G>A has been reported in the literature in multiple individuals affected with Galactosemia, including one homozygote (Ashino_1995, Ozgul_2013). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant results in absent GALT enzyme activity (Ashino_1995, Hirokawa_1999, Riehman_2001, Coelho_2014). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 231 of the GALT protein (p.Arg231His). This variant is present in population databases (rs111033754, gnomAD no frequency). This missense change has been observed in individual(s) with Galactose-1-phosphate uridylyltransferase deficiency (PMID: 7550229, 22944367, 27176039). ClinVar contains an entry for this variant (Variation ID: 25247). 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. Experimental studies have shown that this missense change affects GALT function (PMID: 7550229, 11152465, 25614870). This variant disrupts the p.Arg231 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14518827, 22944367, 25614870, 25814382). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 17, 2023	- -

GALT-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2024

The GALT c.692G>A variant is predicted to result in the amino acid substitution p.Arg231His. This variant has been reported in the homozygous or compound heterozygous state in patients with galactosemia, several of whom were reported to have absent GALT enzyme activity in erythrocytes (Ashino et al. 1995. PubMed ID: 7550229; Boutron et al. 2012. PubMed ID: 22944367; Garcia et al. 2016. PubMed ID: 27176039; Yuzyuk et al. 2018. PubMed ID: 30172461). The p.Arg231His substitution has been reported to reduce protein expression and enzyme activity in functional studies (Ashino et al. 1995. PubMed ID: 7550229; Riehman et al. 2001. PubMed ID: 11152465; Coelho et al. 2014. PubMed ID: 25614870). The p.Arg231 amino acid residue is located at the intersubunit interface and has been predicted to disrupt dimer association and potentially alter monomer stability (Facchiano and Marabotti. 2010. PubMed ID: 20008339; Boutron et al. 2012. PubMed ID: 22944367). A different substitution of the same amino acid (p.Arg231Cys) has also been reported in association with galactosemia (e.g., Boutron et al. 2012. PubMed ID: 22944367; Coelho et al. 2014. PubMed ID: 25614870). This variant is interpreted as pathogenic. -

Galactosemia

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 29, 2017

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 13, 2021

PP3, PP4, PM2, PM5, PS3, PS4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

.;H

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.93

MutPred

0.98

.;Gain of ubiquitination at K229 (P = 0.0557);

MVP

1.0

MPC

2.1

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.98

gMVP

0.98

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over