VCV000291333.48 - ClinVar

NM_000642.3(AGL):c.1759C>T (p.His587Tyr)

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.

Conflicting classifications of pathogenicity
Uncertain significance(7); Benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000642.3(AGL):c.1759C>T (p.His587Tyr)

Variation ID: 291333 Accession: VCV000291333.48

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p21.2 1: 99880655 (GRCh38) [ NCBI UCSC ] 1: 100346211 (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	Dec 6, 2016	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000642.3:c.1759C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000633.2:p.His587Tyr	missense
NM_000028.3:c.1759C>T	NP_000019.2:p.His587Tyr	missense
NM_000643.3:c.1759C>T	NP_000634.2:p.His587Tyr	missense
NM_000644.3:c.1759C>T	NP_000635.2:p.His587Tyr	missense
NM_000646.3:c.1711C>T	NP_000637.2:p.His571Tyr	missense
NM_001425325.1:c.1759C>T	NP_001412254.1:p.His587Tyr	missense
NM_001425326.1:c.1759C>T	NP_001412255.1:p.His587Tyr	missense
NM_001425327.1:c.1558C>T	NP_001412256.1:p.His520Tyr	missense
NM_001425328.1:c.1555C>T	NP_001412257.1:p.His519Tyr	missense
NM_001425329.1:c.1555C>T	NP_001412258.1:p.His519Tyr	missense
NM_001425332.1:c.1381C>T	NP_001412261.1:p.His461Tyr	missense
NC_000001.11:g.99880655C>T
NC_000001.10:g.100346211C>T
NG_012865.1:g.35572C>T

... more HGVS ... less HGVS

Protein change

H587Y, H571Y, H461Y, H519Y, H520Y

Other names

p.His587Tyr

Canonical SPDI

NC_000001.11:99880654: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.

0.00040 (T)

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

1000 Genomes Project 0.00040

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046

1000 Genomes Project 30x 0.00047

Exome Aggregation Consortium (ExAC) 0.00049

The Genome Aggregation Database (gnomAD) 0.00053

The Genome Aggregation Database (gnomAD), exomes 0.00056

Trans-Omics for Precision Medicine (TOPMed) 0.00057

Links

ClinGen: CA966587 dbSNP: rs139488862 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.
AGL		-	-	GRCh38 GRCh37	2679	2699

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.
Glycogen storage disease type III	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jan 31, 2024	RCV000335847.27
not provided	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Sep 14, 2022	RCV001567373.35
Inborn genetic diseases	Uncertain significance (1)	criteria provided, single submitter	Sep 5, 2022	RCV002519359.9

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 (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Glycogen storage disease type III Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000346071.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Feb 03, 2020)	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: SCV000602454.2 First in ClinVar: Sep 30, 2017 Last updated: Jan 26, 2021	Comment: The p.His587Tyr variant (rs139488862) has not been reported in the medical literature; however, it is listed in the ClinVar database as a variant of uncertain … (more) The p.His587Tyr variant (rs139488862) has not been reported in the medical literature; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 291333). It is listed in the NHLBI GO Exome Sequencing Project (ESP) with an overall allele frequency of 0.05% (identified in 6 out of 13,006 chromosomes), and in the Exome Aggregation Consortium (ExAC) browser with an overall frequency of 0.05% (identified in 59 out of 121,372 chromosomes). The histidine at codon 587 is moderately conserved considering 12 species (Alamut software v2.8.1), and computational analyses suggest this variant has a significant effect on AGL protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.His587Tyr variant cannot be determined with certainty. (less)
Uncertain significance (Mar 18, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001791041.1 First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
Uncertain significance (Jul 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glycogen storage disease type III Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002055531.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022
Uncertain significance (Sep 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004227874.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: BS2 Number of individuals with the variant: 2
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glycogen storage disease type III Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000626678.7 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024
Uncertain significance (Sep 05, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003562207.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Comment: The c.1759C>T (p.H587Y) alteration is located in exon 14 (coding exon 13) of the AGL gene. This alteration results from a C to T substitution … (more) The c.1759C>T (p.H587Y) alteration is located in exon 14 (coding exon 13) of the AGL gene. This alteration results from a C to T substitution at nucleotide position 1759, causing the histidine (H) at amino acid position 587 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Jul 01, 2021)	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: SCV001961127.20 First in ClinVar: Oct 08, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Likely benign (Nov 22, 2019)	no assertion criteria provided Method: clinical testing	Glycogen storage disease type III Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457974.1 First in ClinVar: Jan 01, 2021 Last updated: Jan 01, 2021

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

The p.His587Tyr variant (rs139488862) has not been reported in the medical literature; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 291333). It is listed in the NHLBI GO Exome Sequencing Project (ESP) with an overall allele frequency of 0.05% (identified in 6 out of 13,006 chromosomes), and in the Exome Aggregation Consortium (ExAC) browser with an overall frequency of 0.05% (identified in 59 out of 121,372 chromosomes). The histidine at codon 587 is moderately conserved considering 12 species (Alamut software v2.8.1), and computational analyses suggest this variant has a significant effect on AGL protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.His587Tyr variant cannot be determined with certainty.

Comment:

The c.1759C>T (p.H587Y) alteration is located in exon 14 (coding exon 13) of the AGL gene. This alteration results from a C to T substitution at nucleotide position 1759, causing the histidine (H) at amino acid position 587 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs139488862 ...

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_000642.3(AGL):c.1759C>T (p.His587Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs139488862 ...