rs111033728

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000155.4(GALT):c.584T>C(p.Leu195Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000176 in 1,614,078 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

GALT
NM_000155.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15O:1

Conservation

PhyloP100: 6.41

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

PP5

Variant 9-34648353-T-C is Pathogenic according to our data. Variant chr9-34648353-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 25222.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.584T>C	p.Leu195Pro	missense_variant	7/11	ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2 linkuse as main transcript	c.257T>C	p.Leu86Pro	missense_variant	5/9		NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8 linkuse as main transcript	c.584T>C	p.Leu195Pro	missense_variant	7/11	1	NM_000155.4	ENSP00000368119	P1	P07902-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251488

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.000149

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000189

AC:

276

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

118

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000245

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000733

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Pathogenic:8Other:1

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.584T>C;p.(Leu195Pro) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 25222; PMID: 22944367; 20301691; 19375122) - PS4. The variant is present at low allele frequencies population databases (rs111033728– gnomAD 0.0005256%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Leu195Pro) was detected in trans with a Pathogenic variant (PMID: 22944367; 19375122) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic -
not provided, no classification provided	literature only	GeneReviews	-	Severe classic pathogenic variant -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 21, 2022	The GALT c.584T>C; p.Leu195Pro variant (rs111033728), is reported in the literature in the compound heterozygous state with known pathogenic GALT variants in multiple individuals affected with mild to severe galactosemia (Boutron 2012, Kozak 2000, Reichardt 1992). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 25222), and is found in the non-Finnish European population with an allele frequency of 0.015% (17/113,764 alleles) in the Genome Aggregation Database. The leucine at codon 195 is moderately conserved, and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. However, functional analyses of the variant protein show reduced GALT enzymatic activity in vitro (Reichardt 1992). Based on available information, the p.Leu195Pro variant is considered to be pathogenic. References: Boutron A et al. Mutation spectrum in the French cohort of galactosemic patients and structural simulation of 27 novel missense variations. Mol Genet Metab. 2012 Nov;107(3):438-47. Kozak L et al. Mutation analysis of the GALT gene in Czech and Slovak galactosemia populations: identification of six novel mutations, including a stop codon mutation (X380R). Hum Mutat. 2000 Feb;15(2):206. Reichardt JK et al. Characterization of two missense mutations in human galactose-1-phosphate uridyltransferase: different molecular mechanisms for galactosemia. Genomics. 1992 Mar;12(3):596-600. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_000155.3(GALT):c.584T>C(L195P) is classified as pathogenic in the context of galactosemia. Sources cited for classification include the following: PMID 19375122, 1373122, 8598637, 10649501, 10960497, 15841485 and 11397328. Classification of NM_000155.3(GALT):c.584T>C(L195P) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.â€šÃ„Ã¶âˆšÃ‘âˆšÂ£ -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 195 of the GALT protein (p.Leu195Pro). This variant is present in population databases (rs111033728, gnomAD 0.02%). This missense change has been observed in individual(s) with galactosemia (PMID: 1373122, 8598637, 10649501, 19375122, 22944367). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 25222). 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%. Experimental studies have shown that this missense change affects GALT function (PMID: 1373122). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 12, 2024	- -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	GALT: PM3:Strong, PM1, PM2, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2022	A common variant that has been estimated to represent approximately 2% of GALT mutant alleles in the US (Elsas et al., 1998); Published functional studies demonstrate a damaging effect (Reichardt et al. 1992); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10649501, 27415407, 11261429, 27604308, 22975760, 20008339, 17041746, 1373122, 22944367, 8598637, 31194252, 31954591, 34030713, 31589614) -

GALT-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 2024

The GALT c.584T>C variant is predicted to result in the amino acid substitution p.Leu195Pro. This variant has been reported in the compound heterozygous state in patients with classical galactosemia (for example, see Reichardt et al 1992. PubMed ID: 1373122; Berry et al. 2000. PubMed ID: 10960497; Gort et al. 2009. PubMed ID: 19375122). The p.Leu195Pro substitution was reported to abolish enzyme activity in an experimental study (Reichardt et al 1992. PubMed ID: 1373122). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Galactosemia

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

.;D;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

.;M;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.4

D;D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.013

D;D;T

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

0.22

.;B;.

Vest4

0.95

MVP

1.0

MPC

1.3

ClinPred

0.63

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

1.0

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