VCV000030422.27 - ClinVar

NM_013339.4(ALG6):c.391T>C (p.Tyr131His)

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.

(15)

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.

Benign/Likely benign

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.391T>C (p.Tyr131His)

Variation ID: 30422 Accession: VCV000030422.27

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p31.3 1: 63406361 (GRCh38) [ NCBI UCSC ] 1: 63872032 (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	Jul 6, 2014	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_013339.4:c.391T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_037471.2:p.Tyr131His	missense
NC_000001.11:g.63406361T>C
NC_000001.10:g.63872032T>C
NG_008925.2:g.43772T>C
LRG_1260:g.43772T>C
LRG_1260t1:c.391T>C	LRG_1260p1:p.Tyr131His

... more HGVS ... less HGVS

Protein change

Y131H

Other names

Canonical SPDI

NC_000001.11:63406360:T:C

Functional
consequence

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

Global minor allele
frequency (GMAF)

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.

0.01338 (C)

Allele frequency

The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.01338

1000 Genomes Project 30x 0.01359

Trans-Omics for Precision Medicine (TOPMed) 0.02797

Exome Aggregation Consortium (ExAC) 0.02869

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.02922

The Genome Aggregation Database (gnomAD) 0.02935

The Genome Aggregation Database (gnomAD), exomes 0.03021

Links

ClinGen: CA248677

OMIM: 604566.0007

dbSNP: rs35383149

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	770	804

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	Benign/Likely benign (8)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000023375.34
not specified	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Dec 10, 2021	RCV000081558.30
not provided	Likely benign (1)	criteria provided, single submitter	-	RCV004710443.1

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.
Benign (Jan 26, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000517504.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (May 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	ALG6-congenital disorder of glycosylation 1C Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001712306.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Sex: mixed
Likely benign (Dec 10, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002050973.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000311971.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Likely benign (Jan 08, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	ALG6-congenital disorder of glycosylation 1C Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743998.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018
Benign (Feb 26, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000113489.8 First in ClinVar: Jan 17, 2014 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ALG6 Number of individuals with the variant: 2 Sex: mixed
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	ALG6-congenital disorder of glycosylation 1C Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135298.1 First in ClinVar: Jan 10, 2020 Last updated: Jan 10, 2020
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	ALG6-congenital disorder of glycosylation 1C Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001255681.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 21899441‚ 14517965 Comment: 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, … (more) 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Sep 03, 2015)	criteria provided, single submitter (DGD Variant Analysis Guidelines) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000258066.5 First in ClinVar: Jun 28, 2015 Last updated: Dec 24, 2022
Benign (Feb 01, 2024)	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: SCV000649495.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Likely benign (-)	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: SCV005258504.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Likely benign (-)	no assertion criteria provided Method: clinical testing	AllHighlyPenetrant (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000150236.2 First in ClinVar: May 17, 2014 Last updated: Jul 06, 2014	Comment: Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated … (more) Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. (less)
Uncertain significance (May 01, 2011)	no assertion criteria provided Method: literature only	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000044666.6 First in ClinVar: Apr 04, 2013 Last updated: Aug 08, 2022	Publications: PubMed (1) PubMed: 21334936 Hamosh, A. Personal Communication. (more...) Hamosh, A. Personal Communication. 2017. Baltimore, Md. Comment on evidence: This variant, formerly titled CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ic, has been reclassified based on a review of the ExAC database by Hamosh (2017). In … (more) This variant, formerly titled CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ic, has been reclassified based on a review of the ExAC database by Hamosh (2017). In an 18-year-old woman with CDG (see 603147), Miller et al. (2011) identified a homozygous mutation in the ALG6 gene, resulting in a tyr131-to-his (Y131H) substitution. Complementation studies showed that the Y131H mutation only partially rescued defective glycosylation in ALG6-deficient yeast. The patient was hypotonic in infancy and showed developmental delay. Neurologic features included cortical blindness, partial agenesis of the corpus callosum, myoclonic episodes, and cerebellar dysfunction, with dysarthria, wide-based gait, and ataxia. She also had hyperinsulinemic hypoglycemia and gastrointestinal issues. Puberty was slightly delayed, with thelarche at age 13 years and menarche at age 15. At age 18, she had severe premenstrual syndrome, but menses were regular. She had normal secondary sex characteristics. Hormonal laboratory work-up showed no abnormalities and no evidence of increased androgen. Miller et al. (2011) suggested that the variable degree of virilization reported in CDG females may be due to impaired glycosylation and function of the aromatase enzyme (CYP19A1; 107910). The woman described by Miller et al. (2011) was later diagnosed with Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS; 615722) and was found to have a mutation in the NR2F1 gene (Y171X; 132890.0007). Hamosh (2017) noted that the Y131H variant was reported in 3,476 of 121,148 alleles and in 79 homozygotes in the ExAC database (December 12, 2017). (less)
Benign (-)	no assertion criteria provided Method: clinical testing	ALG6-congenital disorder of glycosylation 1C Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000734048.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018
Benign (Jan 13, 2020)	no assertion criteria provided Method: clinical testing	Congenital disorder of glycosylation type 1c Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001456167.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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
Frequency Determination of α-1,3 Glucosyltransferase p.Y131H and p.F304S Polymorphisms in the Croatian Population Revealed Five Novel Single Nucleotide Polymorphisms in the hALG6 Gene.	Goreta SS	Genetic testing and molecular biomarkers	2012	PMID: 21899441
Pubertal development in ALG6 deficiency (congenital disorder of glycosylation type Ic).	Miller BS	Molecular genetics and metabolism	2011	PMID: 21334936
Identification of a frequent variant in ALG6, the cause of Congenital Disorder of Glycosylation-Ic.	Westphal V	Human mutation	2003	PMID: 14517965
Hamosh, A. Personal Communication. 2017. Baltimore, Md.	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ALG6	-	-	-	-

Text-mined citations for rs35383149 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_013339.4(ALG6):c.391T>C (p.Tyr131His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs35383149 ...