19-12899486-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_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 Pathogenic.
Frequency
Consequence
NM_000159.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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GCDH | ENST00000222214.10 | c.1262C>T | p.Ala421Val | missense_variant | Exon 12 of 12 | 1 | NM_000159.4 | ENSP00000222214.4 | ||
SYCE2 | ENST00000293695.8 | c.613-101G>A | intron_variant | Intron 5 of 5 | 1 | NM_001105578.2 | ENSP00000293695.6 |
Frequencies
GnomAD3 genomes AF: 0.000263 AC: 40AN: 152170Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000119 AC: 30AN: 251334Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135858
GnomAD4 exome AF: 0.000106 AC: 155AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 78AN XY: 727246
GnomAD4 genome AF: 0.000263 AC: 40AN: 152170Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 19AN XY: 74326
ClinVar
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:8Other:1
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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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -
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. -
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Founder variant in Pennsylvania Amish -
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. -
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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. -
not provided Pathogenic:4
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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) -
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PP3, PP4, PM2, PM3_strong, PS4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at