rs111033728

chr9-34648353-T-Cchr9-34648353-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L195R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 6.41

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 14 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000155.4
• 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	UniProt
GALT	NM_000155.4	c.584T>C	p.Leu195Pro	missense_variant	7/11	ENST00000378842.8
GALT	NM_001258332.2	c.257T>C	p.Leu86Pro	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000378842.8	c.584T>C	p.Leu195Pro	missense_variant	7/11	1	NM_000155.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152196 Hom.: 0 Cov.: 32

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: 18 AN: 251488 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135920

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.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 118 AN XY: 727242

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: 8 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74352

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.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
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;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
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.‚Äã -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 21, 2021	- -
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	Invitae	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. -

not provided Pathogenic:4

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	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) -
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	- -

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	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	29
Dann	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.61	T
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	D
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

Other links and lift over

dbSNP: rs111033728; hg19: chr9-34648350;