Submissions for variant NM_000284.4(PDHA1):c.937_940dup (p.Ser314fs)

dbSNP: rs137853251

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000196049	SCV000252044	pathogenic	not provided	2017-07-19	criteria provided, single submitter	clinical testing	The c.937_940dupAAGA variant in the PDHA1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.937_940dupAAGA variant causes a frameshift starting with codon Serine 314, changes this amino acid to a Lysine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Ser314LysfsX3. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.937_940dupAAGA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.937_940dupAAGA as a pathogenic variant.
Invitae	RCV001224932	SCV001397159	pathogenic	Pyruvate dehydrogenase E1-alpha deficiency	2019-07-09	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PDHA1 are known to be pathogenic (PMID: 10679936, 21914562). This variant has not been reported in the literature in individuals with PDHA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 214945). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser314Lysfs*3) in the PDHA1 gene. It is expected to result in an absent or disrupted protein product.