Submissions for variant NM_000284.4(PDHA1):c.214C>T (p.Arg72Cys)

dbSNP: rs863224148

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	RCV001796727	SCV002037610	likely pathogenic	Pyruvate dehydrogenase complex deficiency	2021-10-25	reviewed by expert panel	curation	The c.214C>T (p.R72C) variant in PDHA1 has been reported in multiples males with pyruvate dehydrogenase deficiency with phenotypes ranging from childhood onset Leigh syndrome spectrum (PMID: 8664900) to living into adulthood with ataxia, neuropathy, and dystonia (PMID: 21914562). We did not come across any affected female case reports in this extensive literature review. This variant has been reported to be inherited from a healthy mother (PMID: 10679936; case 3-4) and there have been several de novo case reports, as well. Indeed, this variant has been identified as a de novo occurrence (unconfirmed parental relationships) in at least three unrelated individuals with pyruvate dehydrogenase deficiency [PM6; Utilized ClinGen SVI de novo scoring guidance (phenotype consistent but not highly specific); PMID: 10679936, case 3-2; PMID: 10679936, case 3-3; PMID: 21914562, case AM23]. Additionally, this variant has been seen in at least one other individual with documented decreased pyruvate dehydrogenase activity (PP4; Patient 3 in PMID: 15384102 had Leigh syndrome and decreased total PDH complex activity (in native and DCA-activated states) in fibroblast cell line (<3rd percentile of controls). This variant is absent from gnomAD v2.1.1 (PM2). The computational predictor REVEL gives a score of 0.955, which is above the threshold of 0.75, evidence that correlates with impact to PDHA1 function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for pyruvate dehydrogenase deficiency inherited in an X-linked manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on May 20, 2020. PDHA1-specific ACMG/AMP criteria applied: PM2, PM6, PP3, PP4.
GeneDx	RCV000505722	SCV000252036	pathogenic	not provided	2021-08-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10679936, 8664900, 15384102, 21914562, 20002125, 15473177, 7887409, 1301207, 25590979)
Ambry Genetics	RCV000624128	SCV000742478	likely pathogenic	Inborn genetic diseases	2017-04-27	criteria provided, single submitter	clinical testing
Invitae	RCV000692713	SCV000820551	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 72 of the PDHA1 protein (p.Arg72Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pyruvate dehydrogenase E1-alpha deficiency (PMID: 1301207, 7887409, 10679936, 20002125, 25590979). ClinVar contains an entry for this variant (Variation ID: 214938). 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 PDHA1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PDHA1 function (PMID: 1301207, 10679936). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000505722	SCV001247268	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814100	SCV001755612	pathogenic	Abnormality of the mitochondrion	2021-07-10	criteria provided, single submitter	clinical testing
3billion	RCV000692713	SCV002058410	likely pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000214938, PMID:1301207, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.955, 3CNET: 0.913, PP3_P). A missense variant is a common mechanism associated with Pyruvate dehydrogenase E1-alpha deficiency (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Illumina Laboratory Services, Illumina	RCV000692713	SCV002540271	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2021-12-20	criteria provided, single submitter	clinical testing	The PDHA1 c.214C>T (p.Arg72Cys) missense variant, also referred to in the literature as c.328C>T (p.Arg110Cys), results in the substitution of arginine at amino acid position 72 with a cysteine. Across a selection of the available literature, the c.214C>T variant was identified in a hemizygous state in eight male patients with pyruvate dehydrogenase deficiency (Lissens et al. 2000; Cameron et al. 2004; Head et al. 2004; Barnerias et al. 2010; Zhu et al. 2015). Several heterozygous carrier females have been identified with this variant, but their phenotypes were not described (Lissens et al. 2000; Cameron et al. 2004). Affected individuals presented with a range of phenotypes, including Leigh syndrome, hypotonia, dystonia, ataxia, MRI abnormalities, and elevated lactate and pyruvate in blood and CSF. The c.214C>T variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Evaluation of patient fibroblasts showed significantly decreased pyruvate dehydrogenase complex and pyruvate dehydrogenase E1 activity levels compared to controls (Lissens et al. 2000; Cameron et al. 2004; Head et al. 2004; Barnerias et al. 2010). Based on the available evidence, the c.214C>T (p.Arg72Cys) variant is classified as pathogenic for pyruvate dehydrogenase deficiency.