rs367543266

Positions:

chr9-34649466-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000155.4(GALT):c.961C>T(p.His321Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,614,056 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 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GALT
NM_000155.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:2

Conservation

PhyloP100: 4.13

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 16 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000155.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 9-34649466-C-T is Pathogenic according to our data. Variant chr9-34649466-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALT	NM_000155.4 linkuse as main transcript	c.961C>T	p.His321Tyr	missense_variant	10/11	ENST00000378842.8
GALT	NM_001258332.2 linkuse as main transcript	c.634C>T	p.His212Tyr	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000378842.8 linkuse as main transcript	c.961C>T	p.His321Tyr	missense_variant	10/11	1	NM_000155.4	P1	P07902-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00000795

AC:

AN:

251458

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Pathogenic:4Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 18, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 05, 2021	The GALT c.961C>T; p.His321Tyr variant (rs367543266) is reported in the literature in one compound heterozygote and one homozygote affected with galactosemia (Webb 2003, ARUP data). This variant is reported in ClinVar (Variation ID: 25299). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The histidine at codon 321 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.922). Based on available information, this variant is considered to be likely pathogenic. References: Webb AL et al. Verbal dyspraxia and galactosemia. Pediatr Res. 2003 Mar;53(3):396-402. PMID: 12595586. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 17, 2024	Variant summary: GALT c.961C>T (p.His321Tyr) results in a conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, C-terminal domain (IPR005850) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251458 control chromosomes (gnomAD). c.961C>T has been reported in the literature in individuals affected with Galactosemia including homozygous individuals with classic galactosemia (example: Webb_2003, Mir_2022, Yuzyuk_2018). These data indicate that the variant is very likely to be associated with disease. In vitro and in vivo functional studies show that the variant resulted in reduced activity (Yuzyuk_2018). The following publications have been ascertained in the context of this evaluation (PMID: 12595586, 30172461, 27005423). ClinVar contains an entry for this variant (Variation ID: 25299). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2023	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 321 of the GALT protein (p.His321Tyr). This variant is present in population databases (rs367543266, gnomAD 0.007%). This missense change has been observed in individual(s) with galactosemia (PMID: 12595586, 30172461; Invitae). ClinVar contains an entry for this variant (Variation ID: 25299). 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: 30172461). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, flagged submission	clinical testing	Counsyl	Jan 08, 2018	- -

GALT-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2024

The GALT c.961C>T variant is predicted to result in the amino acid substitution p.His321Tyr. This variant has been reported, in the homozygous state or heterozygous with a second rare GALT variant, in patients with galactosemia (Table 1, Webb et al. 2003. PubMed ID: 12595586; Table 2, Yuzyuk et al. 2018. PubMed ID: 30172461; Mir et al. 2023. doi: 10.1159/000528905). Additionally, we have observed this variant in the apparent homozygous state in two siblings with classic galactosemia (Internal Data, PreventionGenetics). The p.His321 amino acid has been reported to play a role in GALT enzyme Zn2+ binding, and the p.His321Tyr substitution is predicted to disrupt this metal binding (McCorvie et al. 2016. PubMed ID: 27005423). Additionally, the p.His321Tyr substitution was reported to reduce in vitro enzyme activity to 3.9% of wild-type (Yuzyuk et al. 2018. PubMed ID: 30172461). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Based on the collective evidence, this variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 21, 2022

PP3, PP4, PM2, PM3, PS3 -

Galactosemia

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Natera, Inc.

Sep 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

.;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.7

.;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.8

D;D

REVEL

Pathogenic

0.92

Sift

Benign

0.089

T;T

Sift4G

Uncertain

0.056

T;T

Polyphen

1.0

.;D

Vest4

0.86

MutPred

0.91

.;Gain of catalytic residue at P325 (P = 0.1317);

MVP

0.99

MPC

0.35

ClinPred

0.96

GERP RS

5.3

Varity_R

0.88

gMVP

0.84

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