VCV000002082.50 - ClinVar

NM_000159.4(GCDH):c.1262C>T (p.Ala421Val)

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.

(13)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000159.4(GCDH):c.1262C>T (p.Ala421Val)

Variation ID: 2082 Accession: VCV000002082.50

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.13 19: 12899486 (GRCh38) [ NCBI UCSC ] 19: 13010300 (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 8, 2016	Nov 24, 2024	Sep 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000159.4:c.1262C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000150.1:p.Ala421Val	missense
NM_001105578.2:c.613-101G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_013976.5:c.1244-214C>T		intron variant
NR_102316.1:n.1425C>T		non-coding transcript variant
NR_102317.1:n.1643C>T		non-coding transcript variant
NC_000019.10:g.12899486C>T
NC_000019.9:g.13010300C>T
NG_009292.1:g.13327C>T
NG_033049.1:g.24787G>A
NG_087357.1:g.255C>T
	Q92947:p.Ala421Val

... more HGVS ... less HGVS

Protein change

A421V

Other names

Canonical SPDI

NC_000019.10:12899485: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.

The Genome Aggregation Database (gnomAD), exomes 0.00012

Exome Aggregation Consortium (ExAC) 0.00019

The Genome Aggregation Database (gnomAD) 0.00027

Trans-Omics for Precision Medicine (TOPMed) 0.00033

Links

ClinGen: CA252095 Genetic Testing Registry (GTR): GTR000167635 UniProtKB: Q92947#VAR_000420 OMIM: 608801.0002 dbSNP: rs121434367 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.
GCDH		-	-	GRCh38 GRCh37	686	913
LOC126862860	-	-	-	GRCh38	-	73
SYCE2		-	-	GRCh38 GRCh37	8	98

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.
Glutaric aciduria, type 1	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Mar 25, 2024	RCV000002163.27
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 4, 2024	RCV000224804.27

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 07, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281590.2 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016
Pathogenic (May 08, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Glutaric aciduria, type 1 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000695716.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017	Publications: PubMed (2) PubMed: 8900227‚ 22728054 Comment: Variant summary: The GCDH c.1262C>T (p.Ala421Val) variant located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 4/4 … (more) Variant summary: The GCDH c.1262C>T (p.Ala421Val) variant located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant . This variant was found in 23/121322 control chromosomes at a frequency of 0.0001896, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). Multiple publications cite the variant in affected GA-1 compound heterozygote and homozygote individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Nov 08, 2021)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021)) Method: clinical testing	Glutaric aciduria, type 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV002060321.2 First in ClinVar: Jan 15, 2022 Last updated: Nov 29, 2022	Publications: PubMed (2) PubMed: 15505393‚ 8900227 Comment: NM_000159.2(GCDH):c.1262C>T(A421V) is a missense variant classified as pathogenic in the context of glutaric acidemia, GCDH-related. A421V has been observed in cases with relevant disease (PMID: … (more) NM_000159.2(GCDH):c.1262C>T(A421V) is a missense variant classified as pathogenic in the context of glutaric acidemia, GCDH-related. A421V has been observed in cases with relevant disease (PMID: 15505393, 8900227). Functional assessments of this variant are available in the literature (PMID: 8900227). A421V has been observed in population frequency databases (gnomAD: NFE 0.02%). In summary, NM_000159.2(GCDH):c.1262C>T(A421V) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Aug 09, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glutaric aciduria, type 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893506.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Glutaric aciduria, type 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000410872.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (5) PubMed: 8900227‚ 17478444‚ 19630565‚ 22728054‚ 10699052 Comment: The GCDH c.1262C>T (p.Ala421Val) variant is a well-known founder variant among the Old Order Amish of Lancaster County, Pennsylvania, where approximately one in 500 children … (more) The GCDH c.1262C>T (p.Ala421Val) variant is a well-known founder variant among the Old Order Amish of Lancaster County, Pennsylvania, where approximately one in 500 children is homozygous for this variant (Strauss et al. 2007; Strauss et al. 2009). Across three studies that included 138 total Amish and European-ancestry individuals with glutaric acidemia type 1 (GA1), the p.Ala421Val variant is reported in 21 total individuals, including eight homozygotes, eight compound heterozygotes, and five in whom the zygosity is not stated (Biery et al. 1996; Zschocke et al. 2000; Viau et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00033 in the European (non-Finnish) population from the Exome Aggregation Consortium. Functional studies in E. Coli showed that the p.Ala421Val variant resulted in enzyme activity that was 20% to 40% that of the wild type protein (Biery et al. 1996). Based on the collective evidence, the p.Ala421Val variant is classified as pathogenic for glutaric acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Jul 12, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321708.8 First in ClinVar: Jun 08, 2016 Last updated: Aug 05, 2023	Comment: Published functional studies found this variant is associated with significantly reduced enzyme activity compared to wild-type (Biery et al., 1996); Reported as a common pathogenic … (more) Published functional studies found this variant is associated with significantly reduced enzyme activity compared to wild-type (Biery et al., 1996); Reported as a common pathogenic variant among individuals of the Old Order Amish population of Lancaster, Pennsylvania (Biery et al., 1996); 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: 22728054, 30838298, 8900227, 28438223, 31028937, 31589614, 32777384, 32240488) (less)
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Glutaric aciduria, type 1 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000935988.6 First in ClinVar: Aug 13, 2019 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 8900227‚ 18926513‚ 28438223 Comment: This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 421 of the GCDH protein (p.Ala421Val). … (more) This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 421 of the GCDH protein (p.Ala421Val). This variant is present in population databases (rs121434367, gnomAD 0.03%). This missense change has been observed in individual(s) with glutaric acidemia (PMID: 8900227, 18926513, 28438223). It is commonly reported in individuals of Amish ancestry (PMID: 8900227, 18926513, 28438223). ClinVar contains an entry for this variant (Variation ID: 2082). 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 GCDH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCDH function (PMID: 8900227). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glutaric aciduria, type 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001530161.2 First in ClinVar: Mar 22, 2021 Last updated: Jun 17, 2024
Pathogenic (Aug 01, 2020)	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: SCV001501240.23 First in ClinVar: Mar 14, 2021 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Sep 04, 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: SCV005413329.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (8) PubMed: 28438223‚ 30838298‚ 31028937‚ 32240488‚ 32777384‚ 36913764‚ 37020324‚ 8900227 Comment: PP3, PP4, PM2, PM3_strong, PS4 Number of individuals with the variant: 1
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Glutaric acidemia type 1 Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001456402.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (Jul 01, 2007)	no assertion criteria provided Method: literature only	GLUTARIC ACIDEMIA I Affected status: not provided Allele origin: germline	OMIM Accession: SCV000022321.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 13, 2017	Publications: PubMed (2) PubMed: 8900227‚ 17478444 Comment on evidence: In the Old Order Amish of Lancaster County, Pennsylvania, Biery et al. (1996) found that the type I glutaric acidemia (GA1; 231670) was caused in … (more) In the Old Order Amish of Lancaster County, Pennsylvania, Biery et al. (1996) found that the type I glutaric acidemia (GA1; 231670) was caused in all cases by homozygosity for a 1298C-T transition in the GCDH gene, resulting in an ala421-to-val (A421V) amino acid substitution. In 4 non-Amish patients with glutaric acidemia type I, Biery et al. (1996) found compound heterozygosity for mutations in the GCDH gene, with 1 allele being the A421V 'Amish' gene; all these patients had some central European ancestry. Expression studies of the A421V mutation in E. coli showed reduced enzyme activity, which the authors suggested was due to impaired association of enzyme subunits. Strauss et al. (2007) referred to the Amish mutation as 1296C-T. (less)
not provided (-)	no classification provided Method: literature only	Glutaric aciduria, type 1 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV001133284.2 First in ClinVar: Jan 06, 2020 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 31536184‚ 1951469 BookShelf: NBK546575 BookShelf: NBK546575 Comment: Founder variant in Pennsylvania Amish
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Comment:

Variant summary: The GCDH c.1262C>T (p.Ala421Val) variant located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 4/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a damaging outcome for this variant . This variant was found in 23/121322 control chromosomes at a frequency of 0.0001896, which does not exceed the estimated maximal expected allele frequency of a pathogenic GCDH variant (0.0035355). Multiple publications cite the variant in affected GA-1 compound heterozygote and homozygote individuals. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

NM_000159.2(GCDH):c.1262C>T(A421V) is a missense variant classified as pathogenic in the context of glutaric acidemia, GCDH-related. A421V has been observed in cases with relevant disease (PMID: 15505393, 8900227). Functional assessments of this variant are available in the literature (PMID: 8900227). A421V has been observed in population frequency databases (gnomAD: NFE 0.02%). In summary, NM_000159.2(GCDH):c.1262C>T(A421V) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

The GCDH c.1262C>T (p.Ala421Val) variant is a well-known founder variant among the Old Order Amish of Lancaster County, Pennsylvania, where approximately one in 500 children is homozygous for this variant (Strauss et al. 2007; Strauss et al. 2009). Across three studies that included 138 total Amish and European-ancestry individuals with glutaric acidemia type 1 (GA1), the p.Ala421Val variant is reported in 21 total individuals, including eight homozygotes, eight compound heterozygotes, and five in whom the zygosity is not stated (Biery et al. 1996; Zschocke et al. 2000; Viau et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.00033 in the European (non-Finnish) population from the Exome Aggregation Consortium. Functional studies in E. Coli showed that the p.Ala421Val variant resulted in enzyme activity that was 20% to 40% that of the wild type protein (Biery et al. 1996). Based on the collective evidence, the p.Ala421Val variant is classified as pathogenic for glutaric acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

Published functional studies found this variant is associated with significantly reduced enzyme activity compared to wild-type (Biery et al., 1996); Reported as a common pathogenic variant among individuals of the Old Order Amish population of Lancaster, Pennsylvania (Biery et al., 1996); 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: 22728054, 30838298, 8900227, 28438223, 31028937, 31589614, 32777384, 32240488)

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 421 of the GCDH protein (p.Ala421Val). This variant is present in population databases (rs121434367, gnomAD 0.03%). This missense change has been observed in individual(s) with glutaric acidemia (PMID: 8900227, 18926513, 28438223). It is commonly reported in individuals of Amish ancestry (PMID: 8900227, 18926513, 28438223). ClinVar contains an entry for this variant (Variation ID: 2082). 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 GCDH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GCDH function (PMID: 8900227). For these reasons, this variant has been classified as Pathogenic.

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
Exploring genotype-phenotype correlations in glutaric aciduria type 1.	Schuurmans IME	Journal of inherited metabolic disease	2023	PMID: 37020324
2-Methylglutaconic acid as a biomarker in routine urine organic acids leading to the diagnosis of glutaric acidemia type I in a low excretor.	Wongkittichote P	Molecular genetics and metabolism	2023	PMID: 36913764
Glutaric aciduria type 1: Genetic and phenotypic spectrum in 53 patients.	Gürbüz BB	European journal of medical genetics	2020	PMID: 32777384
Molecular and biochemical study of glutaric aciduria type 1 in 49 Russian families: nine novel mutations in the GCDH gene.	Kurkina MV	Metabolic brain disease	2020	PMID: 32240488
Development of a Novel Next-Generation Sequencing Assay for Carrier Screening in Old Order Amish and Mennonite Populations of Pennsylvania.	Crowgey EL	The Journal of molecular diagnostics : JMD	2019	PMID: 31028937
Atypical Glutaric Aciduria Type I with Hemidystonia and Asymmetric Radiological Findings Misdiagnosed as an Ischemic Stroke.	Demailly D	Movement disorders clinical practice	2018	PMID: 30838298
Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity.	Boy N	Orphanet journal of rare diseases	2017	PMID: 28438223
Glutaric acidemia type 1: outcomes before and after expanded newborn screening.	Viau K	Molecular genetics and metabolism	2012	PMID: 22728054
Genetics, medicine, and the Plain people.	Strauss KA	Annual review of genomics and human genetics	2009	PMID: 19630565
Genetic mapping of glutaric aciduria, type 3, to chromosome 7 and identification of mutations in c7orf10.	Sherman EA	American journal of human genetics	2008	PMID: 18926513
Multimodal imaging of striatal degeneration in Amish patients with glutaryl-CoA dehydrogenase deficiency.	Strauss KA	Brain : a journal of neurology	2007	PMID: 17478444
Correlation of genotype and phenotype in glutaryl-CoA dehydrogenase deficiency.	Christensen E	Journal of inherited metabolic disease	2004	PMID: 15505393
Mutation analysis in glutaric aciduria type I.	Zschocke J	Journal of medical genetics	2000	PMID: 10699052
Gene structure and mutations of glutaryl-coenzyme A dehydrogenase: impaired association of enzyme subunits that is due to an A421V substitution causes glutaric acidemia type I in the Amish.	Biery BJ	American journal of human genetics	1996	PMID: 8900227
Glutaric aciduria type I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of Lancaster County, Pennsylvania.	Morton DH	American journal of medical genetics	1991	PMID: 1951469
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Text-mined citations for rs121434367 ...

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_000159.4(GCDH):c.1262C>T (p.Ala421Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121434367 ...