9-34647247-G-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3PP5

The NM_000155.4(GALT):c.241G>C(p.Ala81Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,780 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. A81T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GALT
NM_000155.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 9.20

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

classic galactosemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
galactosemia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health

GALT links:

ENSG00000258728 (HGNC:):

ENSG00000258728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr9-34647247-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 25141.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 104 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 0.91493 (below the threshold of 3.09). Trascript score misZ: 1.8645 (below the threshold of 3.09). GenCC associations: The gene is linked to galactosemia, classic galactosemia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.84

PP5

Variant 9-34647247-G-C is Pathogenic according to our data. Variant chr9-34647247-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1330596.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALT	NM_000155.4 link	c.241G>C	p.Ala81Pro	missense_variant	Exon 2 of 11	ENST00000378842.8	NP_000146.2	P07902-1B2RAT6A0A0S2Z3Y7
GALT	NM_001258332.2 link	c.39G>C	p.Glu13Asp	missense_variant	Exon 2 of 9		NP_001245261.1	P07902-2B2RAT6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8 link	c.241G>C	p.Ala81Pro	missense_variant	Exon 2 of 11	1	NM_000155.4	ENSP00000368119.4		P07902-1
ENSG00000258728	ENST00000556278.1 link	c.241G>C	p.Ala81Pro	missense_variant	Exon 2 of 8	5		ENSP00000451792.1		G3V4G9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251164

AF XY:

0.00000737

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111970

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Pathogenic:3

May 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 23, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GALT c.241G>C; p.Ala81Pro variant (rs111033665) is reported to be in compound heterozygous state with a pathogenic GALT variant p.Gln188Arg in the literature in an individual affected with mild galactosemia (Ohlsson 2019). This variant is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 81 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.761). Additionally, another variant at this codon (c.241G>A; p.Ala81Thr) has been reported in individuals with galactosemia. Based on available information, the p.Ala81Pro variant is considered to be likely pathogenic. References: Ohlsson A et al. Heterogeneity of disease-causing variants in the Swedish galactosemia population: Identification of 16 novel GALT variants. J Inherit Metab Dis. 2019 Sep;42(5):1008-1018. PMID: 31194895. -

Aug 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala81 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1427861). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 1330596). This missense change has been observed in individual(s) with galactose-1-phosphate uridylyltransferase deficiency (PMID: 31194895). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs111033665, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 81 of the GALT protein (p.Ala81Pro). -

not specified

Uncertain:1

Jun 24, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GALT c.241G>C (p.Ala81Pro) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 8e-06 in 251164 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.241G>C has been reported in an individual affected with Galactosemia (e.g., Ohlsson_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31194895). ClinVar contains an entry for this variant (Variation ID: 1330596). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Sep 25, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PM2_moderate, PM3_supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Pathogenic

1.3

PhyloP100

9.2

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.6

N;N

REVEL

Pathogenic

0.76

Sift

Benign

0.28

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.041

B;.

Vest4

0.69

MutPred

0.68

Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);

MVP

0.99

MPC

1.1

ClinPred

0.93

GERP RS

5.5

Varity_R

0.90

gMVP

0.94

Mutation Taster

=5/95

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over