rs367543266

chr9-34649466-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 4.13

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 Likely_pathogenic. Variant got 9 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 25299.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2, Pathogenic=2}.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152186 Hom.: 0 Cov.: 31

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: 2 AN: 251458 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135902

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: 3 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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: 2 AN: 152186 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

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: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Pathogenic:3 Uncertain:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 08, 2023	- -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2017	Variant summary: The GALT c.961C>T (p.His321Tyr) variant located in the Galactose-1-phosphate uridyl transferase, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. However, a publication, McCorvie_2016, predicts the variant to "remove interactions with zinc ion, steric clash with Leu37." This variant was found in 1/121402 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic GALT variant (0.0028868). The variant of interest has been reported in two affected individuals, one compound heterozygote (Webb_2003) indicating the variant to be a "leaky" mutation. Along with a clinical diagnostic laboratory classifying the variant as "pathogenic" and indicating a homozygous occurrence in an affected patient. Furthermore, multiple missense variants nearby, p.Ala320Thr, p.Pro325Leu, p.Arg328Cys, and p.Arg333Trp, have been classified by LCA as likely pathogenic/pathogenic, suggesting the area is a mutational hotspot important for protein function. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as VUS - possibly pathogenic variant. -
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, no assertion criteria provided

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	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
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	D
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

Other links and lift over

dbSNP: rs367543266; hg19: chr9-34649463;