Submissions for variant NM_001256007.3(PNPLA8):c.2275_2276del (p.Leu759fs)

dbSNP: rs774184465

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414528	SCV000492198	uncertain significance	not specified	2016-11-23	criteria provided, single submitter	clinical testing	The c.2275_2276delCT variant in the PNPLA8 gene has been reported previously in an individual with a suspected mitochondrial myopathy, with progressive muscle weakness, hypotonia, seizures, poor weight gain, and lactic acidosis, who was compound heterozygous for the c.2275_2276delCT variant and another loss of function variant (Saunders et al., 2015). The c.2275_2276delCT variant causes a frameshift starting with codon Leucine 759, changes this amino acid to an Alanine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Leu759AlafsX4. This variant is predicted to cause loss of normal protein function through protein truncation. The c.2275_2276delCT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2275_2276delCT as a variant of uncertain significance.
Invitae	RCV002517632	SCV003440155	pathogenic	not provided	2022-07-12	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs774184465, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Leu759Alafs*4) in the PNPLA8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the PNPLA8 protein. This premature translational stop signal has been observed in individual(s) with mitochondrial myopathy with lactic acidosis (PMID: 25512002, 29681094). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 190128). This variant is also known as c.1975_1976delAG.
Baylor Genetics	RCV000170362	SCV003836185	pathogenic	Mitochondrial myopathy-lactic acidosis-deafness syndrome	2021-02-05	criteria provided, single submitter	clinical testing
OMIM	RCV000170362	SCV000222771	pathogenic	Mitochondrial myopathy-lactic acidosis-deafness syndrome	2015-03-01	no assertion criteria provided	literature only