19-12899485-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP5 BP4

The NM_000159.4(GCDH):c.1261G>A(p.Ala421Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,614,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A421V) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: GCDH NM_000159.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2 O:1
• Conservation: PhyloP100: 7.88

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 Likely_pathogenic. Variant got 6 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 chr19-12899486-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.
• PP5: Variant 19-12899485-G-A is Pathogenic according to our data. Variant chr19-12899485-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 285973.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=2, Uncertain_significance=2, not_provided=1}. Variant chr19-12899485-G-A is described in Lovd as [Pathogenic]. Variant chr19-12899485-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.06658238).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.1261G>A	p.Ala421Thr	missense_variant	12/12	ENST00000222214.10
SYCE2	NM_001105578.2	c.613-100C>T		intron_variant		ENST00000293695.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.1261G>A	p.Ala421Thr	missense_variant	12/12	1	NM_000159.4	P1
SYCE2	ENST00000293695.8	c.613-100C>T		intron_variant		1	NM_001105578.2	P1

Frequencies

GnomAD3 genomes AF: 0.000545 AC: 83 AN: 152158 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 251284 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135834

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000800 AC: 117 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000660 AC XY: 48 AN XY: 727246

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152276 Hom.: 1 Cov.: 31 AF XY: 0.000524 AC XY: 39 AN XY: 74442

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000167 Hom.: 1

Bravo AF: 0.000756

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:4 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 421 of the GCDH protein (p.Ala421Thr). This variant is present in population databases (rs151201155, gnomAD 0.2%). This missense change has been observed in individual(s) with GCDH-related conditions (PMID: 27672653, 28302372). ClinVar contains an entry for this variant (Variation ID: 285973). 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 GCDH protein function with a negative predictive value of 80%. This variant disrupts the p.Ala421 amino acid residue in GCDH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8900227, 15505393, 28438223). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 23, 2022	Variant summary: GCDH c.1261G>A (p.Ala421Thr) results in a non-conservative amino acid change located in the C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00055 in 150930 control chromosomes, predominantly within the African or African-American subpopulation at a frequency of 0.0018 in the gnomAD database (v3.1 dataset), including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in GCDH causing Glutaric Acidemia Type 1 (0.0035), allowing no conclusion about variant significance. The variant, c.1261G>A, has been reported in the literature in multiple compound heterozygous individuals affected with Glutaric Acidemia Type 1 (Christensen_2004, Tsai_2017, Wahab_2016, Dong_2020, Lin_2021, Guenzel_2021). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated decreased enzymatic activity both in patient derived fibroblasts (Christensen_2004) and in bacterial expression systems (Goodman_1998, Westover_2003), although the level of residual activity varied greatly between these experimental methods. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=3), and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 11, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 26, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant classified as Pathogenic and reported on 06-18-2021 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 09, 2022	- -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2023	Identified in individuals with glutaric aciduria type 1 in published literature, although clinical information was not provided (Goodman et al., 1998); Published functional studies found A421T is associated with significantly reduced enzyme activity (Goodman et al., 1998; Westover et al., 2003); 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: 27672653, 28302372, 25087612, 9711871, 23891399, 12948740, 28062662, 15505393, 32306145, 32005694, 34258142, 34344405) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.067	T;T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.7	D;.
REVEL	Pathogenic	0.90
Sift	Benign	0.047	D;.
Sift4G	Benign	0.52	T;T
Polyphen		0.90	P;P
Vest4		0.70
MVP		0.98
MPC		0.72
ClinPred		0.073	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.71
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs151201155; hg19: chr19-13010299;