VCV000092522.27 - ClinVar

NM_000155.4(GALT):c.772C>T (p.Arg258Cys)

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.

(9)

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_000155.4(GALT):c.772C>T (p.Arg258Cys)

Variation ID: 92522 Accession: VCV000092522.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9p13.3 9: 34648846 (GRCh38) [ NCBI UCSC ] 9: 34648843 (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	Jun 28, 2015	Jun 17, 2024	Mar 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000155.4:c.772C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000146.2:p.Arg258Cys	missense
NM_001258332.2:c.445C>T	NP_001245261.1:p.Arg149Cys	missense
NC_000009.12:g.34648846C>T
NC_000009.11:g.34648843C>T
NG_009029.2:g.7258C>T
NG_028966.1:g.1662C>T
	P07902:p.Arg258Cys

... more HGVS ... less HGVS

Protein change

R258C, R149C

Other names

Canonical SPDI

NC_000009.12:34648845:C:T

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.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00003

Exome Aggregation Consortium (ExAC) 0.00005

Links

ClinGen: CA266764 UniProtKB: P07902#VAR_002605 dbSNP: rs368166217 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.
GALT		-	-	GRCh38 GRCh37	718	882

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 UDPglucose-hexose-1-phosphate uridylyltransferase	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Mar 30, 2024	RCV000078235.28
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jun 9, 2023	RCV000493672.22

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.
Pathogenic (Jul 16, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110073.8 First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALT Number of individuals with the variant: 7 Sex: mixed
Likely pathogenic (Aug 01, 2017)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Not Provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000885498.1 First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018
Likely pathogenic (Mar 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226597.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (16) PubMed: 10384398‚ 10408771‚ 10960497‚ 11261429‚ 15633893‚ 20008339‚ 23690308‚ 25087612‚ 29350350‚ 30718057‚ 30808388‚ 31194895‚ 33636947‚ 34485021‚ 35118398‚ 35677809 Comment: PP3, PP4, PM2, PM3, PS4_moderate Number of individuals with the variant: 2
Pathogenic (Jan 08, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000931179.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 10960497‚ 30718057 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the GALT protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the GALT protein (p.Arg258Cys). This variant is present in population databases (rs368166217, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of galactosemia (PMID: 10960497, 30718057; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92522). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 30, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004198490.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jun 09, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000582974.7 First in ClinVar: Jul 02, 2017 Last updated: Jun 17, 2023	Comment: Identified in an individual with galactosemia who harbored a second variant in the GALT gene. This individual had >5% residual enzyme activity in erythrocytes and … (more) Identified in an individual with galactosemia who harbored a second variant in the GALT gene. This individual had >5% residual enzyme activity in erythrocytes and a Duarte-like isoelectric focusing banding pattern (Berry et al., 2000); Considered a milder GALT variant (Korner et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 30718057, 15633893, 30808388, 31194895, 10408771, 20008339, 23690308, 10960497, 17876724, 29350350, 11261429, 10384398, 31194252, 34426522, 35677809) (less)
Likely pathogenic (Mar 13, 2019)	no assertion criteria provided Method: clinical testing	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000800530.2 First in ClinVar: Jun 28, 2015 Last updated: Dec 23, 2019	Publications: PubMed (5) PubMed: 17876724‚ 23690308‚ 30808388‚ 10960497‚ 15633893
Likely pathogenic (Oct 11, 2020)	no assertion criteria provided Method: clinical testing	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Affected status: yes Allele origin: germline	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City Accession: SCV001469241.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Uncertain significance (Apr 09, 2021)	Flagged submission flagged submission (ACMG Guidelines, 2015) Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003808590.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the GALT protein (p.Arg258Cys). This variant is present in population databases (rs368166217, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of galactosemia (PMID: 10960497, 30718057; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92522). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Comment:

Identified in an individual with galactosemia who harbored a second variant in the GALT gene. This individual had >5% residual enzyme activity in erythrocytes and a Duarte-like isoelectric focusing banding pattern (Berry et al., 2000); Considered a milder GALT variant (Korner et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 30718057, 15633893, 30808388, 31194895, 10408771, 20008339, 23690308, 10960497, 17876724, 29350350, 11261429, 10384398, 31194252, 34426522, 35677809)

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
Translating principles of precision medicine into speech-language pathology: Clinical trial of a proactive speech and language intervention for infants with classic galactosemia.	Peter B	HGG advances	2022	PMID: 35677809
Pathophysiology and management of classic galactosemic primary ovarian insufficiency.	Hagen-Lillevik S	Reproduction & fertility	2021	PMID: 35118398
Abnormal N-glycan fucosylation, galactosylation, and sialylation of IgG in adults with classical galactosemia, influence of dietary galactose intake.	Treacy EP	JIMD reports	2021	PMID: 34485021
Heterogeneity of disease-causing variants in the Swedish galactosemia population: Identification of 16 novel GALT variants.	Ohlsson A	Journal of inherited metabolic disease	2019	PMID: 31194895
Deficits of facial emotion recognition and visual information processing in adult patients with classical galactosemia.	Korner M	Orphanet journal of rare diseases	2019	PMID: 30808388
The ability of an LC-MS/MS-based erythrocyte GALT enzyme assay to predict the phenotype in subjects with GALT deficiency.	Demirbas D	Molecular genetics and metabolism	2019	PMID: 30718057
Galactose-1-Phosphate Uridyltransferase Activities in Different Genotypes: A Retrospective Analysis of 927 Samples.	Yuzyuk T	The journal of applied laboratory medicine	2018	PMID: 33636947
Biochemical changes and clinical outcomes in 34 patients with classic galactosemia.	Yuzyuk T	Journal of inherited metabolic disease	2018	PMID: 29350350
Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results.	Tabor HK	American journal of human genetics	2014	PMID: 25087612
Modifiers of ovarian function in girls and women with classic galactosemia.	Spencer JB	The Journal of clinical endocrinology and metabolism	2013	PMID: 23690308
Analysis of galactosemia-linked mutations of GALT enzyme using a computational biology approach.	Facchiano A	Protein engineering, design & selection : PEDS	2010	PMID: 20008339
Combination of enzyme analysis, allele-specific PCR and sequencing to detect mutations in the GALT gene.	Calderon FR	Journal of inherited metabolic disease	2007	PMID: 17876724
Molecular and biochemical basis for variants and deficiency of GALT: report of 4 novel mutations.	Shin YS	Bratislavske lekarske listy	2004	PMID: 15633893
Galactose breath testing distinguishes variant and severe galactose-1-phosphate uridyltransferase genotypes.	Berry GT	Pediatric research	2000	PMID: 10960497
Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene.	Tyfield L	Human mutation	1999	PMID: 10408771
Molecular and biochemical basis for variants and deficiency forms of galactose-1-phosphate uridyltransferase.	Shin YS	Journal of inherited metabolic disease	1999	PMID: 10384398
The molecular biology of galactosemia.	Elsas LJ 2nd	Genetics in medicine : official journal of the American College of Medical Genetics	1998	PMID: 11261429
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=GALT	-	-	-	-
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Text-mined citations for rs368166217 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000155.4(GALT):c.772C>T (p.Arg258Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs368166217 ...