NM_000154.2(GALK1):c.410del (p.Gly137fs) AND Deficiency of galactokinase

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jan 28, 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:: RCV000667929.14

Allele description [Variation Report for NM_000154.2(GALK1):c.410del (p.Gly137fs)]

NM_000154.2(GALK1):c.410del (p.Gly137fs)

Gene:

GALK1:galactokinase 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

17q25.1

Genomic location:

Preferred name:

NM_000154.2(GALK1):c.410del (p.Gly137fs)

HGVS:

NC_000017.11:g.75763390del
NG_008079.1:g.6815del
NM_000154.2:c.410delMANE SELECT
NP_000145.1:p.Gly137fs
LRG_1430t1:c.410del
LRG_1430p1:p.Gly137fs
NC_000017.10:g.73759466del
NC_000017.10:g.73759471del
NC_000017.11:g.75763385delC
NM_000154.1:c.410del
NM_000154.1:c.410delG

Protein change:

G137fs

Links:

dbSNP: rs767329054

NCBI 1000 Genomes Browser:

rs767329054

Molecular consequence:

NM_000154.2:c.410del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Deficiency of galactokinase
Synonyms:: GALACTOSEMIA II; Galactosemia 2; Hereditary galactokinase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009255; MedGen: C0268155; Orphanet: 352; OMIM: 230200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000792456	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Likely pathogenic (Jun 27, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10570908, 20405025 Citation Link,
SCV001411291	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7670469, 10790206, 10570908, 20405025, 28492532
SCV002058230	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:10570908,
SCV002088896	Natera, Inc.	no assertion criteria provided	Pathogenic (Mar 13, 2020)	germline	clinical testing
SCV004197926	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 26, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848235	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 17, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10570908, 20405025, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
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

Cloning of the galactokinase cDNA and identification of mutations in two families with cataracts.

Stambolian D, Ai Y, Sidjanin D, Nesburn K, Sathe G, Rosenberg M, Bergsma DJ.

Nat Genet. 1995 Jul;10(3):307-12.

PubMed [citation]

PMID:: 7670469

Novel mutations in 13 probands with galactokinase deficiency.

Kolosha V, Anoia E, de Cespedes C, Gitzelmann R, Shih L, Casco T, Saborio M, Trejos R, Buist N, Tedesco T, Skach W, Mitelmann O, Ledee D, Huang K, Stambolian D.

Hum Mutat. 2000;15(5):447-53.

PubMed [citation]

PMID:: 10790206

See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000792456.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001411291.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Gly137Valfs*27) in the GALK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALK1 are known to be pathogenic (PMID: 7670469, 10790206). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with GALK1-related conditions (PMID: 10570908, 20405025). ClinVar contains an entry for this variant (Variation ID: 552633). For these reasons, this variant has been 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

From 3billion, SCV002058230.1

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

Description

Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000552633, PMID:10570908). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Natera, Inc., SCV002088896.1

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

#	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, SCV004197926.2

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848235.1

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

Description

The p.Gly137ValfsX27 variant in GALK1 has been reported in the homozygous state in 6 affected members of one Pakistani family with early-onset cataracts (Yasmeen 2010). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 137 and leads to a premature termination codon 27 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for galactokinase deficiency in an autosomal recessive manner. ACMG/AMP criteria applied: PVS1_Strong, PP1_Strong, PM2, PM3_Supporting.

#	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 20, 2024

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