Submissions for variant NM_001256007.3(PNPLA8):c.929T>C (p.Val310Ala)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002472217	SCV002769309	uncertain significance	Mitochondrial myopathy-lactic acidosis-deafness syndrome	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_001256007.2(PNPLA8):c.929T>C in exon 3 of 11 of the PNPLA8 gene. This substitution is predicted to create a minor amino acid change from valine to alanine at position 310 of the protein, NP_001242936.1(PNPLA8):p.(Val310Ala). The valine at this position has very high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0050% (14 heterozygotes, 0 homozygotes). The variant has not been previously reported in clinical cases. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV003108121	SCV003780953	uncertain significance	not provided	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 310 of the PNPLA8 protein (p.Val310Ala). This variant is present in population databases (rs143802109, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PNPLA8-related conditions. ClinVar contains an entry for this variant (Variation ID: 1805799). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004958556	SCV005469856	uncertain significance	Inborn genetic diseases	2024-09-26	criteria provided, single submitter	clinical testing	The c.929T>C (p.V310A) alteration is located in exon 4 (coding exon 1) of the PNPLA8 gene. This alteration results from a T to C substitution at nucleotide position 929, causing the valine (V) at amino acid position 310 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.