Submissions for variant NM_000284.4(PDHA1):c.677G>A (p.Arg226His)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004766779	SCV005380409	likely pathogenic	Pyruvate dehydrogenase complex deficiency	2024-08-22	criteria provided, single submitter	clinical testing	Variant summary: PDHA1 c.677G>A (p.Arg226His) results in a non-conservative amino acid change located in the Dehydrogenase, E1 component domain (IPR001017) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183500 control chromosomes. c.677G>A has been reported in the literature in the hemizygous state in at least 1 individual affected with Pyruvate Dehydrogenase Deficiency (example, Shin_2017). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in patient derived tissues (example, Shin_2017). The following publication has been ascertained in the context of this evaluation (PMID: 28918066). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic.