VCV000552633.25 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 552633 Accession: VCV000552633.25

Type and length

Deletion, 1 bp

Location

Cytogenetic: 17q25.1 17: 75763385 (GRCh38) [ NCBI UCSC ] 17: 73759466 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 5, 2018	Oct 20, 2024	Jan 28, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000154.2:c.410del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000145.1:p.Gly137fs	frameshift
NM_000154.1:c.410del
NC_000017.11:g.75763390del
NC_000017.10:g.73759471del
NG_008079.1:g.6815del
LRG_1430t1:c.410del	LRG_1430p1:p.Gly137fs

... more HGVS ... less HGVS

Protein change

G137fs

Other names

Canonical SPDI

NC_000017.11:75763384:CCCCCC:CCCCC

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs767329054 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GALK1		-	-	GRCh38 GRCh37	489	985

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Deficiency of galactokinase	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 28, 2024	RCV000667929.14
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 1, 2023	RCV003326487.11

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jun 27, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Deficiency of galactokinase Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000792456.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (2) PubMed: 10570908‚ 20405025
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of galactokinase Affected status: yes Allele origin: germline	3billion Accession: SCV002058230.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:10570908 PMID:10570908 Comment: 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 … (more) 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. (less) Clinical Features: Blindness (present) , Cataract (present) , Cataract (present) , Congenital blindness (present)
Pathogenic (Jan 28, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Deficiency of galactokinase Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001411291.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 7670469‚ 10790206‚ 10570908‚ 20405025 Comment: This sequence change creates a premature translational stop signal (p.Gly137Valfs27) in the GALK1 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gly137Valfs27) 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. (less)
Pathogenic (Sep 17, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of galactokinase (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848235.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (2) PubMed: 10570908‚ 20405025 Comment: 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). … (more) 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. (less)
Pathogenic (Jan 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of galactokinase Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004197926.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jul 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004033584.11 First in ClinVar: Sep 16, 2023 Last updated: Oct 20, 2024	Comment: GALK1: PVS1, PM2, PM3, PP4 Number of individuals with the variant: 2
Pathogenic (Mar 13, 2020)	no assertion criteria provided Method: clinical testing	Deficiency of galactokinase Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002088896.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Autosomal recessive congenital cataract in consanguineous Pakistani families is associated with mutations in GALK1.	Yasmeen A	Molecular vision	2010	PMID: 20405025
Novel mutations in 13 probands with galactokinase deficiency.	Kolosha V	Human mutation	2000	PMID: 10790206
Molecular characterization of galactokinase deficiency in Japanese patients.	Asada M	Journal of human genetics	1999	PMID: 10570908
Cloning of the galactokinase cDNA and identification of mutations in two families with cataracts.	Stambolian D	Nature genetics	1995	PMID: 7670469

Text-mined citations for rs767329054 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs767329054 ...