NM_000154.2(GALK1):c.593C>T (p.Ala198Val) AND Deficiency of galactokinase

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(3) (Last evaluated: Nov 12, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000005987.11

Allele description [Variation Report for NM_000154.2(GALK1):c.593C>T (p.Ala198Val)]

NM_000154.2(GALK1):c.593C>T (p.Ala198Val)

Gene:
GALK1:galactokinase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q25.1
Genomic location:
Preferred name:
NM_000154.2(GALK1):c.593C>T (p.Ala198Val)
HGVS:
  • NC_000017.11:g.75763032G>A
  • NG_008079.1:g.7168C>T
  • NM_000154.2:c.593C>TMANE SELECT
  • NP_000145.1:p.Ala198Val
  • LRG_1430t1:c.593C>T
  • LRG_1430p1:p.Ala198Val
  • NC_000017.10:g.73759113G>A
  • NM_000154.1:c.593C>T
  • P51570:p.Ala198Val
Protein change:
A198V; ALA198VAL
Links:
UniProtKB: P51570#VAR_015746; OMIM: 604313.0006; dbSNP: rs80084721
NCBI 1000 Genomes Browser:
rs80084721
Molecular consequence:
  • NM_000154.2:c.593C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Deficiency of galactokinase (GALAC2)
Synonyms:
GALACTOSEMIA II; Galactosemia 2; Hereditary galactokinase deficiency
Identifiers:
MONDO: MONDO:0009255; MedGen: C0268155; Orphanet: 352; OMIM: 230200

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000026169OMIMno assertion criteria providedPathogenic
(Apr 1, 2001)
germlineliterature only

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

SCV000631404Invitaecriteria provided, single submitter
Uncertain significance
(Nov 12, 2019)
germlineclinical testing

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

SCV000800800Counsylcriteria provided, single submitter
Likely benign
(Dec 20, 2017)
unknownclinical testing

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

Citation Link,

SCV001140835Mendelicscriteria provided, single submitter
Uncertain significance
(May 28, 2019)
unknownclinical testing

Citation Link,

SCV001285771Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Apr 27, 2017)
germlineclinical testing

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

Citation Link,

SCV001459342Natera, Inc.no assertion criteria providedUncertain significance
(Jan 7, 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
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

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

The effect of a Pro²⁸Thr point mutation on the local structure and stability of human galactokinase enzyme-a theoretical study.

Jójárt B, Szori M, Izsák R, Marsi I, László A, Csizmadia IG, Viskolcz B.

J Mol Model. 2011 Oct;17(10):2639-49. doi: 10.1007/s00894-011-0958-y. Epub 2011 Jan 25.

PubMed [citation]
PMID:
21264483
See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000026169.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 3 infants with mild galactokinase deficiency (GALAC2; 230200), Okano et al. (2001) identified a 593C-T transition in exon 4 of the GALK1 gene, resulting in an ala198-to-val (A198V) substitution. This variant, designated Osaka, was found to have an appreciable frequency in Japanese and Koreans, with a lower incidence in Taiwanese and Chinese and no incidence in blacks or whites from the United States. It appeared to be related to cataract in elderly individuals.

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

From Invitae, SCV000631404.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces alanine with valine at codon 198 of the GALK1 protein (p.Ala198Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs80084721, ExAC 1.5%). This variant, also known as the 'Osaka' variant, is reported at a relatively high frequency in the Japanese (4.1%) and Korean (2.8%) populations; individuals from these populations who are homozygous for this variant have been observed to have reduced galactokinase activity (~20% of normal) and mild galactokinase deficiency (PMID: 11231902). In addition, this variant is found at a higher frequency (7.8%) in Japanese adults with bilateral cataracts than in general Japanese population (4.1%) (PMID: 11231902). This data suggests that the Osaka variant may be associated with an increased risk for bilateral cataracts, although larger population studies are needed to confirm this association. ClinVar contains an entry for this variant (Variation ID: 5633). Experimental studies have demonstrated that this missense change does not significantly affect the enzymatic activity of the GALK1 protein (PMID: 12694189, 11231902). However, expression analysis in crude blood extracts from individuals who are homozygous for this variant indicate that this variant results in an 80% reduction in expression of the GALK1 protein (PMID: 11231902). In summary, this variant is a rare missense change that has been shown to result in a partial loss of GALK1 protein expression and enzymatic activity in vivo. While this variant does not appear to cause classic galactokinase deficiency, it may confer an increased risk for bilateral cataracts in adults. However, larger population studies are needed to demonstrate this conclusively. Therefore, this missense change has been classified as a Variant of Uncertain Significance.

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

From Counsyl, SCV000800800.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Mendelics, SCV001140835.1

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

From Illumina Clinical Services Laboratory,Illumina, SCV001285771.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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

From Natera, Inc., SCV001459342.1

#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: Aug 27, 2021

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