X-19357664-A-C
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1
The NM_000284.4(PDHA1):c.844A>C(p.Met282Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00804 in 1,207,672 control chromosomes in the GnomAD database, including 708 homozygotes. There are 3,235 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.
Frequency
Consequence
NM_000284.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PDHA1 | NM_000284.4 | c.844A>C | p.Met282Leu | missense_variant | 9/11 | ENST00000422285.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PDHA1 | ENST00000422285.7 | c.844A>C | p.Met282Leu | missense_variant | 9/11 | 1 | NM_000284.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00953 AC: 1065AN: 111782Hom.: 86 Cov.: 23 AF XY: 0.0104 AC XY: 353AN XY: 33974
GnomAD3 exomes AF: 0.0214 AC: 3930AN: 183510Hom.: 331 AF XY: 0.0191 AC XY: 1298AN XY: 67940
GnomAD4 exome AF: 0.00789 AC: 8643AN: 1095835Hom.: 623 Cov.: 28 AF XY: 0.00797 AC XY: 2880AN XY: 361269
GnomAD4 genome ? AF: 0.00950 AC: 1063AN: 111837Hom.: 85 Cov.: 23 AF XY: 0.0104 AC XY: 355AN XY: 34039
ClinVar
Submissions by phenotype
Pyruvate dehydrogenase E1-alpha deficiency Pathogenic:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 15, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 27, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 20, 2021 | Variant summary: PDHA1 c.844A>C (p.Met282Leu) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.021 in 183510 control chromosomes, predominantly at a frequency of 0.26 within the East Asian subpopulation in the gnomAD database, including 329 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 831999.87 fold of the estimated maximal expected allele frequency for a pathogenic variant in PDHA1 causing Pyruvate Dehydrogenase Deficiency phenotype (3.1e-07), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, all but one classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 02, 2016 | - - |
Pyruvate dehydrogenase complex deficiency Benign:2
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, reviewed by expert panel | curation | ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen | Apr 02, 2021 | The allele frequency of the c.844A>C (p.M282L) variant in the PDHA1 gene is 0.207% in gnomAD, including 1,436 hemizygotes. This allele frequency, and the frequency with which it is seen in hemizygotes in the general population are high enough to be classified as benign based on thresholds defined by the ClinGen PDHA1 Variant Curation Expert Panel (>0.092%; gnomAD >16 hemizygotes). In summary, this variant meets criteria to be classified as benign for PDHA1- related pyruvate dehydrogenase deficiency in an X-linked manner. PDHA1-specific ACMG/AMP criteria applied: (BA1, BS2). This was reviewed with the PDHA1 expert panel on 2/16/2021 and approved on 2/16/2021. - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 25, 2015 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 04, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at