Submissions for variant NM_001256007.3(PNPLA8):c.2227C>T (p.Gln743Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004512009	SCV005008567	likely pathogenic	Inborn genetic diseases	2023-12-14	criteria provided, single submitter	clinical testing	The c.2227C>T (p.Q743*) alteration, located in exon 12 (coding exon 9) of the PNPLA8 gene, consists of a C to T substitution at nucleotide position 2227. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 743. This alteration occurs at the 3' terminus of the PNPLA8 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 5% of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as likely pathogenic.
GeneDx	RCV004723600	SCV005333342	likely pathogenic	not provided	2023-11-28	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation as the last 40 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Fields 2022[Poster])