rs367543270

chr9-34648864-CTA-TAG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000155.4(GALT):c.790_792inv(p.Leu264Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALT NM_000155.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.26

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-34648864-CTA-TAG is Pathogenic according to our data. Variant chr9-34648864-CTA-TAG is described in ClinVar as [Pathogenic]. Clinvar id is 459627.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.790_792inv	p.Leu264Ter	stop_gained	8/11	ENST00000378842.8
GALT	NM_001258332.2	c.463_465inv	p.Leu155Ter	stop_gained	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALT	ENST00000378842.8	c.790_792inv	p.Leu264Ter	stop_gained	8/11	1	NM_000155.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 19, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 30, 2023	PP4, PM2, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2021	Observed in apparent homozygous state in a patient with a confirmed diagnosis of classic galactosemia (Elsas et al., 1998); Not observed in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11261429, 30718057, 11754113, 10408771) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2023	The GALT c.790_792inv; p.Leu264Ter variant (rs367543270), also known as L264X, is reported in the literature in individuals affected with galactosemia (Demirbas 2019, Elsas 1998, Yang 2002). This variant is also reported in ClinVar (Variation ID: 459627), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in individuals with galactosemia and are considered pathogenic (Boutron 2012, Demirbas 2019, Tyfield 1999). Based on available information, this 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. PMID: 22944367. Demirbas D et al. The ability of an LC-MS/MS-based erythrocyte GALT enzyme assay to predict the phenotype in subjects with GALT deficiency. Mol Genet Metab. 2019 Apr;126(4):368-376. PMID: 30718057. Elsas LJ 2nd and Lai K. The molecular biology of galactosemia. Genet Med. 1998 Nov-Dec;1(1):40-8. PMID: 11261429. Tyfield L et al. Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat. 1999;13(6):417-30. PMID: 10408771. Yang YP et al. Molecular analysis in newborns from Texas affected with galactosemia. Hum Mutat. 2002 Jan;19(1):82-3. PMID: 11754113. -

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

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 19, 2022	This sequence change creates a premature translational stop signal ( p.Leu264*) in the GALT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALT are known to be pathogenic (PMID: 22944367). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with galactosemia (PMID: 11261429, 11754113). ClinVar contains an entry for this variant (Variation ID: 1074150). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2020	Variant summary: GALT c.790_792delinsTAG (p.Leu264X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 245500 control chromosomes. c.790_792delinsTAG has been reported in the literature in individuals affected with Galactosemia (example, Elsas_1998, Yang_2002, Demirbas_2019 and an external laboratory database). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs367543270; hg19: chr9-34648861;