NM_000155.4(GALT):c.626A>C (p.Tyr209Ser) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Aug 12, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000022168.12

Allele description [Variation Report for NM_000155.4(GALT):c.626A>C (p.Tyr209Ser)]

NM_000155.4(GALT):c.626A>C (p.Tyr209Ser)

Gene:

GALT:galactose-1-phosphate uridylyltransferase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9p13.3

Genomic location:

Preferred name:

NM_000155.4(GALT):c.626A>C (p.Tyr209Ser)

HGVS:

NC_000009.12:g.34648395A>C
NG_009029.2:g.6807A>C
NG_028966.1:g.1211A>C
NM_000155.4:c.626A>CMANE SELECT
NM_001258332.2:c.299A>C
NP_000146.2:p.Tyr209Ser
NP_001245261.1:p.Tyr100Ser
NC_000009.11:g.34648392A>C
NM_000155.3:c.626A>C
P07902:p.Tyr209Ser
c.626A>C (p.Tyr209Ser)

Protein change:

Y100S

Links:

UniProtKB: P07902#VAR_002597; dbSNP: rs111033744

NCBI 1000 Genomes Browser:

rs111033744

Molecular consequence:

NM_000155.4:c.626A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258332.2:c.299A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase
Synonyms:: GALACTOSE-1-PHOSPHATE URIDYLYLTRANSFERASE DEFICIENCY; Galactose-1-phosphate uridyltransferase deficiency; Transferase Deficiency Galactosemia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009258; MedGen: C0268151; Orphanet: 352; Orphanet: 79239; OMIM: 230400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001575145	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 13, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10399107, 11397328, 16540753, 16765930, 22944367, 34030713, 28492532
SCV004198560	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 4, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005380609	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 12, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10399107, 22944367, 16765930 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001575145

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 13, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004198560

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 4, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV005380609

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 12, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Outcomes analysis of verbal dyspraxia in classic galactosemia.

Robertson A, Singh RH, Guerrero NV, Hundley M, Elsas LJ.

Genet Med. 2000 Mar-Apr;2(2):142-8.

PubMed [citation]

PMID:: 11397328

Prevention of a molecular misdiagnosis in galactosemia.

Barbouth D, Slepak T, Klapper H, Lai K, Elsas LJ.

Genet Med. 2006 Mar;8(3):178-82.

PubMed [citation]

PMID:: 16540753

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001575145.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr209 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10399107, 11397328, 16540753). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 25232). This missense change has been observed in individual(s) with classic galactosemia (PMID: 16765930, 22944367, 34030713). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 209 of the GALT protein (p.Tyr209Ser).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004198560.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005380609.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: GALT c.626A>C (p.Tyr209Ser) results in a non-conservative amino acid change located in the Galactose-1-phosphate uridyl transferase, C-terminal domain (IPR005850) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251482 control chromosomes. c.626A>C has been reported in the literature in individuals affected with Galactosemia (examples: Zekanowski_1999, Mirzajani_2006, Boutron_2012). These data indicate that the variant is likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.626A>G, p.Tyr209Cys), supporting the critical relevance of codon 209 to GALT protein function. The following publications have been ascertained in the context of this evaluation (PMID: 16765930, 22944367, 10399107). ClinVar contains an entry for this variant (Variation ID: 25232). Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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