rs121434367

Positions:

• chr19-12899486-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_000159.4(GCDH):​c.1262C>T​(p.Ala421Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A421T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 7.69

Genes affected

GCDH (HGNC:4189): (glutaryl-CoA dehydrogenase) The protein encoded by this gene belongs to the acyl-CoA dehydrogenase family. It catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. The enzyme exists in the mitochondrial matrix as a homotetramer of 45-kD subunits. Mutations in this gene result in the metabolic disorder glutaric aciduria type 1, which is also known as glutaric acidemia type I. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 12. [provided by RefSeq, Mar 2013]

SYCE2 (HGNC:27411): (synaptonemal complex central element protein 2) The protein encoded by this gene is part of the synaptonemal complex formed between homologous chromosomes during meiotic prophase. The encoded protein associates with SYCP1 and SYCE1 and is found only where chromosome cores are synapsed. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000159.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-12899485-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 285973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 19-12899486-C-T is Pathogenic according to our data. Variant chr19-12899486-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12899486-C-T is described in Lovd as [Pathogenic]. Variant chr19-12899486-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.1262C>T	p.Ala421Val	missense_variant	12/12	ENST00000222214.10
SYCE2	NM_001105578.2	c.613-101G>A		intron_variant		ENST00000293695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.1262C>T	p.Ala421Val	missense_variant	12/12	1	NM_000159.4	P1
SYCE2	ENST00000293695.8	c.613-101G>A		intron_variant		1	NM_001105578.2	P1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152170 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251334 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000106 AC: 155 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 78 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000117

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152170 Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 19 AN XY: 74326

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000318 Hom.: 0

Bravo AF: 0.000332

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:8 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 25, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	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. -
not provided, no classification provided	literature only	GeneReviews	-	Founder variant in Pennsylvania Amish -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 09, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 07, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;M
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.99	D;D
Vest4		0.89
MVP		0.98
MPC		1.1
ClinPred		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121434367; hg19: chr19-13010300;