9-34647858-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 15P and 1B. PM1 PM2 PM5 PP3 PP5_Very_Strong BP4

The NM_000155.4(GALT):c.404C>T(p.Ser135Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00017 in 1,614,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S135W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000093 (0 hom.)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23 O:1
• Conservation: PhyloP100: 7.00

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 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr9-34647858-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 25172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 9-34647858-C-T is Pathogenic according to our data. Variant chr9-34647858-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-34647858-C-T is described in Lovd as [Pathogenic]. Variant chr9-34647858-C-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.10496533).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALT	NM_000155.4	c.404C>T	p.Ser135Leu	missense_variant	5/11	ENST00000378842.8
GALT	NM_001258332.2	c.77C>T	p.Ser26Leu	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000378842.8	c.404C>T	p.Ser135Leu	missense_variant	5/11	1	NM_000155.4	P1

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000247 AC: 62 AN: 251492 Hom.: 0 AF XY: 0.000228 AC XY: 31 AN XY: 135922

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.000202

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: 0.00

GnomAD4 exome AF: 0.0000930 AC: 136 AN: 1461866 Hom.: 0 Cov.: 33 AF XY: 0.0000743 AC XY: 54 AN XY: 727238

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74488

Gnomad4 AFR AF: 0.00310

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000175 Hom.: 0

Bravo AF: 0.000941

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000346 AC: 42

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:16 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 14, 2020	- -
Likely pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 15, 2019	NM_000155.3(GALT):c.404C>T(S135L) is classified as pathogenic in the context of galactosemia. Sources cited for classification include the following: PMID 10070616, 11754113, 19418241, 8551426, 7887417, 12208137, 1610789 and 11152465. Classification of NM_000155.3(GALT):c.404C>T(S135L) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 135 of the GALT protein (p.Ser135Leu). This variant is present in population databases (rs111033690, gnomAD 0.4%). This missense change has been observed in individual(s) with galactosemia (PMID: 7887417, 8551426, 12350230, 22461411, 22944367, 27176039, 28065439). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3618). 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: 7887417, 11152465, 12208137). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 15, 2023	The GALT c.404C>T; p.Ser135Leu variant (rs111033690) has been reported in multiple individuals with GALT deficiency (Fridovich-Keil 1995, Lai 1996). Functional characterization of the variant protein indicates strongly reduced enzymatic activity and thermostability (Coelho 2014, Fridovich-Keil 1995, Lai 1996, Riehman 2001). This variant is also reported in ClinVar (Variation ID: 3618). It is observed in the general population with an overall allele frequency of 0.03% (94/282882 alleles) in the Genome Aggregation Database. The serine at codon 135 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.921). Based on available information, this variant is considered to be pathogenic. References: Coelho AI et al. Functional and structural impact of the most prevalent missense mutations in classic galactosemia. Mol Genet Genomic Med. 2014 Nov;2(6):484-96. PMID: 25614870. Fridovich-Keil JL et al. Identification and functional analysis of three distinct mutations in the human galactose-1-phosphate uridyltransferase gene associated with galactosemia in a single family. Am J Hum Genet. 1995 Mar;56(3):640-6. PMID: 7887417. Lai K et al. A prevalent mutation for galactosemia among black Americans. J Pediatr. 1996 Jan;128(1):89-95. PMID: 8551426. Riehman K et al. Relationship between genotype, activity, and galactose sensitivity in yeast expressing patient alleles of human galactose-1-phosphate uridylyltransferase. J Biol Chem. 2001 Apr 6;276(14):10634-40. PMID: 11152465. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.025%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003618). Different missense changes at the same codon (p.Ser135Pro, p.Ser135Trp) have been reported to be associated with GALT related disorder (ClinVar ID: VCV000025172 / PMID: 15841485, 22944367). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided, no classification provided	literature only	GeneReviews	-	Most common clinical pathogenic variant in African Americans & South Africans -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 28, 2021	PS3, PP3, PM3_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.404C>T;p.(Ser135Leu) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3618; PMID: 20301691; 28065439; 27176039; 10070616; 7887417) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 9323558) - PS3_supporting. The variant is present at low allele frequencies population databases (rs111033690– gnomAD 0.009002%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Ser135Leu) was detected in trans with a Pathogenic variant (PMID: 28065439; 27176039; 10070616) - PM3_strong. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (Clinvar ID: 25172) -PM5. 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 -
Pathogenic, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 18, 2017	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Galactosemia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Present at frequency compatible with disease prevalence in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:11754113) (PMID:22461411). PS3 => Well-established functional studies show a deleterious effect (PMID:7887417,25614870). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	Apr 01, 2023	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2020	Functional analysis found S135L is associated with significantly reduced enzyme activity (Fridovich-Keil et al., 1995; Coelho et al., 2014); In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 1610789, 9323558, 12552079, 22975760, 25614870, 25087612, 11754113, 12208137, 12350230, 29302074, 34391645, 8551426, 11152465, 7887417, 20008339, 10070616, 19418241, 28065439, 27176039, 22944367, 22461411, 1373122, 31954591, 30275481, 34030713, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 18, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 01, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2021

The c.404C>T (p.S135L) alteration is located in exon 5 (coding exon 5) of the GALT gene. This alteration results from a C to T substitution at nucleotide position 404, causing the serine (S) at amino acid position 135 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD) database, the GALT c.404C>T alteration was observed in 0.03% (94/282882) of total alleles studied, with a frequency of 0.35% (87/24960) in the African subpopulation. This mutation has been reported in multiple individuals in the homozygous and compound heterozygous states with galactosemia (Henderson, 2002; Boutron, 2012; Garcia, 2016; Welsink-Karssies, 2020). In yeast and E. coli, GALT activity was reduced compared to wild type (Fridovich-Keil, 1995; Riehman, 2001; Coelho, 2014). The p.S135L alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Galactosemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 27, 2020

ACMG classification criteria: PS3, PS4, PM2, PM3, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.94	.;P
Vest4		0.92
MVP		0.99
MPC		1.7
ClinPred		0.14	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs111033690; hg19: chr9-34647855;