VCV000632114.14 - ClinVar

NM_013339.4(ALG6):c.482A>G (p.Tyr161Cys)

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.

(8)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_013339.4(ALG6):c.482A>G (p.Tyr161Cys)

Variation ID: 632114 Accession: VCV000632114.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p31.3 1: 63407114 (GRCh38) [ NCBI UCSC ] 1: 63872785 (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	May 27, 2019	Nov 24, 2024	Mar 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_013339.4:c.482A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_037471.2:p.Tyr161Cys	missense
NC_000001.11:g.63407114A>G
NC_000001.10:g.63872785A>G
NG_008925.2:g.44525A>G
LRG_1260:g.44525A>G
LRG_1260t1:c.482A>G	LRG_1260p1:p.Tyr161Cys

... more HGVS ... less HGVS

Protein change

Y161C

Other names

p.Tyr161Cys

Canonical SPDI

NC_000001.11:63407113:A:G

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.

Exome Aggregation Consortium (ExAC) 0.00006

The Genome Aggregation Database (gnomAD) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00008

Trans-Omics for Precision Medicine (TOPMed) 0.00009

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

dbSNP: rs201354339 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.
ALG6		-	-	GRCh38 GRCh37	771	805

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.
ALG6-congenital disorder of glycosylation 1C	Uncertain significance (6)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV000778991.14
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Mar 15, 2024	RCV004691295.2

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.
Uncertain significance (Feb 06, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ALG6-congenital disorder of glycosylation 1C Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001523916.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Oct 29, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	ALG6-congenital disorder of glycosylation 1C Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000915430.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (2) PubMed: 20398363‚ 26117549 Comment: The ALG6 c.482A>G (p.Tyr161Cys) variant is a missense variant that has been reported in a homozygous state in at least one individual from Saudi Arabia … (more) The ALG6 c.482A>G (p.Tyr161Cys) variant is a missense variant that has been reported in a homozygous state in at least one individual from Saudi Arabia who was diagnosed with congenital disorder of glycosylation type Ic (Al-Owain et al. 2010; Mohamed et al. 2015). This variant is reported at a frequency of 0.000620 in the Other population of the Genome Aggregation Database. The evidence for the p.Tyr161Cys variant is limited. It is therefore classified as a variant of uncertain significance but suspicious for pathogenicity for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Uncertain significance (Oct 07, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	ALG6-congenital disorder of glycosylation 1C Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000952196.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 20398363 Comment: This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 161 of the ALG6 protein … (more) This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 161 of the ALG6 protein (p.Tyr161Cys). This variant is present in population databases (rs201354339, gnomAD 0.01%). This missense change has been observed in individual(s) with ALG6-CDG (congenital disorder of glycosylation) (PMID: 20398363). ClinVar contains an entry for this variant (Variation ID: 632114). 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 not expected to disrupt ALG6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Jul 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ALG6-congenital disorder of glycosylation 1C Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002781901.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ALG6-congenital disorder of glycosylation 1C Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806653.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005186729.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024
Uncertain significance (Mar 15, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005408005.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (9) PubMed: 20398363‚ 22838182‚ 23430515‚ 26117549‚ 27287710‚ 27884173‚ 28940310‚ 34426522‚ 37239976 Comment: PP3 Number of individuals with the variant: 1
Uncertain significance (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Congenital disorder of glycosylation type 1c Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001456277.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

The ALG6 c.482A>G (p.Tyr161Cys) variant is a missense variant that has been reported in a homozygous state in at least one individual from Saudi Arabia who was diagnosed with congenital disorder of glycosylation type Ic (Al-Owain et al. 2010; Mohamed et al. 2015). This variant is reported at a frequency of 0.000620 in the Other population of the Genome Aggregation Database. The evidence for the p.Tyr161Cys variant is limited. It is therefore classified as a variant of uncertain significance but suspicious for pathogenicity for congenital disorders of glycosylation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 161 of the ALG6 protein (p.Tyr161Cys). This variant is present in population databases (rs201354339, gnomAD 0.01%). This missense change has been observed in individual(s) with ALG6-CDG (congenital disorder of glycosylation) (PMID: 20398363). ClinVar contains an entry for this variant (Variation ID: 632114). 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 not expected to disrupt ALG6 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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
Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review.	Conte F	International journal of molecular sciences	2023	PMID: 37239976
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Single-center experience of N-linked Congenital Disorders of Glycosylation with a Summary of Molecularly Characterized Cases in Arabs.	Bastaki F	Annals of human genetics	2018	PMID: 28940310
Revisiting the morbid genome of Mendelian disorders.	Abouelhoda M	Genome biology	2016	PMID: 27884173
ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies.	Morava E	Journal of inherited metabolic disease	2016	PMID: 27287710
Neurometabolic Disorders-Related Early Childhood Epilepsy: A Single-Center Experience in Saudi Arabia.	Mohamed S	Pediatrics and neonatology	2015	PMID: 26117549
ALG6-CDG in South Africa: Genotype-Phenotype Description of Five Novel Patients.	Dercksen M	JIMD reports	2013	PMID: 23430515
Insights into complexity of congenital disorders of glycosylation.	Goreta SS	Biochemia medica	2012	PMID: 22838182
A novel mutation and first report of dilated cardiomyopathy in ALG6-CDG (CDG-Ic): a case report.	Al-Owain M	Orphanet journal of rare diseases	2010	PMID: 20398363

Text-mined citations for rs201354339 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_013339.4(ALG6):c.482A>G (p.Tyr161Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201354339 ...