NM_000155.4(GALT):c.974C>T (p.Pro325Leu) AND Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Dec 5, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000022250.7

Allele description [Variation Report for NM_000155.4(GALT):c.974C>T (p.Pro325Leu)]

NM_000155.4(GALT):c.974C>T (p.Pro325Leu)

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.974C>T (p.Pro325Leu)
HGVS:
  • NC_000009.12:g.34649479C>T
  • NG_009029.2:g.7891C>T
  • NG_028966.1:g.2295C>T
  • NM_000155.4:c.974C>TMANE SELECT
  • NM_001258332.2:c.647C>T
  • NP_000146.2:p.Pro325Leu
  • NP_001245261.1:p.Pro216Leu
  • NC_000009.11:g.34649476C>T
  • NM_000155.3:c.974C>T
  • P07902:p.Pro325Leu
Protein change:
P216L
Links:
UniProtKB: P07902#VAR_002621; dbSNP: rs111033794
NCBI 1000 Genomes Browser:
rs111033794
Molecular consequence:
  • NM_000155.4:c.974C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258332.2:c.647C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase (GALAC1)
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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000755884Invitaecriteria provided, single submitter
Pathogenic
(Dec 5, 2019)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000798721Counsylcriteria provided, single submitter
Likely pathogenic
(Mar 22, 2018)
unknownclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV001363671Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Aug 5, 2019)
germlineclinical testing

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

Citation Link,

SCV002024163PerkinElmer Genomicsno assertion criteria providedPathogenic
(Sep 19, 2020)
germlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene.

Tyfield L, Reichardt J, Fridovich-Keil J, Croke DT, Elsas LJ 2nd, Strobl W, Kozak L, Coskun T, Novelli G, Okano Y, Zekanowski C, Shin Y, Boleda MD.

Hum Mutat. 1999;13(6):417-30. Review.

PubMed [citation]
PMID:
10408771
See all PubMed Citations (9)

Details of each submission

From Invitae, SCV000755884.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces proline with leucine at codon 325 of the GALT protein (p.Pro325Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs111033794, ExAC 0.009%). This variant has been observed on the opposite chromosome (in trans) from other pathogenic GALT variants in individuals affected with galactosemia (PMID: 9222760, 10573007). In addition, it has been reported as homozygous or in combination with other GALT variants in individuals affected with galactosemia (PMID: 10573007, 22944367, 20213376). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 25305). Experimental studies have shown that this missense change impairs GALT enzyme activity in vitro (PMID: 10573007). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Counsyl, SCV000798721.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363671.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

Variant summary: GALT c.974C>T (p.Pro325Leu) results in a non-conservative amino acid change located in the 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 allele was found at a frequency of 1.2e-05 in 251618 control chromosomes (gnomAD). c.974C>T has been reported in the literature in multiple individuals (in homozygous and compound heterozygous state) affected with Galactosemia (e.g. Greber-Platzer_1997, Hirokawa_1999, Milankovics_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication (Hirokawa_1999) reports experimental evidence using a cell line evaluating an impact on protein function and demonstrated reduced GALT activity (11% compared to WT controls). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (1x) or likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From PerkinElmer Genomics, SCV002024163.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 28, 2021

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