Submissions for variant NM_000305.3(PON2):c.358A>G (p.Ile120Val)

gnomAD frequency: 0.00129  dbSNP: rs116397473

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000896009	SCV001040080	likely benign	not provided	2019-12-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000896009	SCV001550147	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PON2 p.Ile120Val variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs116397473) and was also found in control databases in 127 of 282812 chromosomes at a frequency of 0.000449 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 114 of 24970 chromosomes (freq: 0.004565), Other in 3 of 7224 chromosomes (freq: 0.000415) and Latino in 10 of 35434 chromosomes (freq: 0.000282), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish) or South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ile120 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.