NM_000155.4(GALT):c.403T>G (p.Ser135Ala) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 13, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002022361.5

Allele description [Variation Report for NM_000155.4(GALT):c.403T>G (p.Ser135Ala)]

NM_000155.4(GALT):c.403T>G (p.Ser135Ala)

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.403T>G (p.Ser135Ala)

HGVS:

NC_000009.12:g.34647857T>G
NG_009029.2:g.6269T>G
NG_028966.1:g.673T>G
NM_000155.4:c.403T>GMANE SELECT
NM_001258332.2:c.76T>G
NP_000146.2:p.Ser135Ala
NP_001245261.1:p.Ser26Ala
NC_000009.11:g.34647854T>G

Protein change:

S135A

Links:

dbSNP: rs2132343082

NCBI 1000 Genomes Browser:

rs2132343082

Molecular consequence:

NM_000155.4:c.403T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001258332.2:c.76T>G - 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
SCV002296368	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Feb 13, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 7887417, 28065439, 22944367, 22461411, 27176039, 11152465, 12208137, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002296368

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Feb 13, 2021)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

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

Citations

PubMed

Identification and functional analysis of three distinct mutations in the human galactose-1-phosphate uridyltransferase gene associated with galactosemia in a single family.

Fridovich-Keil JL, Langley SD, Mazur LA, Lennon JC, Dembure PP, Elsas JL 2nd.

Am J Hum Genet. 1995 Mar;56(3):640-6.

PubMed [citation]

PMID:: 7887417
PMCID:: PMC1801186

Nine years of newborn screening for classical galactosemia in the Netherlands: Effectiveness of screening methods, and identification of patients with previously unreported phenotypes.

Welling L, Boelen A, Derks TG, Schielen PC, de Vries M, Williams M, Wijburg FA, Bosch AM.

Mol Genet Metab. 2017 Mar;120(3):223-228. doi: 10.1016/j.ymgme.2016.12.012. Epub 2016 Dec 29.

PubMed [citation]

PMID:: 28065439

See all PubMed Citations (8)

Details of each submission

From Invitae, SCV002296368.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This variant is not present in population databases (ExAC no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser135 amino acid residue in GALT. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7887417, 28065439, 22944367, 22461411, 27176039, 11152465, 12208137). 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. This variant has not been reported in the literature in individuals with GALT-related conditions. This sequence change replaces serine with alanine at codon 135 of the GALT protein (p.Ser135Ala). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and alanine.

#	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: Mar 5, 2024

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