Submissions for variant NM_174936.4(PCSK9):c.1496G>T (p.Arg499Leu)

dbSNP: rs143394031

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001181296	SCV001346407	uncertain significance	Familial hypercholesterolemia	2018-11-16	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the C-terminal CM1 domain of the PCSK9 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 3/239136 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001876023	SCV002277887	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2022-03-18	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PCSK9 protein function. ClinVar contains an entry for this variant (Variation ID: 921735). This missense change has been observed in individual(s) with low LDL cholesterol (PMID: 24507775). This variant is present in population databases (rs143394031, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 499 of the PCSK9 protein (p.Arg499Leu).
Fulgent Genetics, Fulgent Genetics	RCV001876023	SCV002794471	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2021-09-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003163418	SCV003858511	uncertain significance	Cardiovascular phenotype	2023-01-25	criteria provided, single submitter	clinical testing	The p.R499L variant (also known as c.1496G>T), located in coding exon 9 of the PCSK9 gene, results from a G to T substitution at nucleotide position 1496. The arginine at codon 499 is replaced by leucine, an amino acid with dissimilar properties. This altertation has been reported in a low LDL-C cohort (Lange LA et al. Am J Hum Genet, 2014 Feb;94:233-45). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004528403	SCV004105767	uncertain significance	PCSK9-related disorder	2023-05-30	criteria provided, single submitter	clinical testing	The PCSK9 c.1496G>T variant is predicted to result in the amino acid substitution p.Arg499Leu. This variant has been documented in an individual with extremely low LDL cholesterol (LDL-C) (Lange et al. 2014. PubMed ID: 24507775). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-55524313-G-T). A different missense variant affecting the same amino acid (p.Arg499His) has been reported to segregate with high LDL-C phenotype and familial hypercholesterolemia in at least one large family pedigree, and also has functional studies supporting its pathogenicity (Sánchez-Hernández et al. 2019. PubMed ID: 31518966; Di Taranto et al. 2021. PubMed ID: 34297352). At this time, the clinical significance of the p.Arg499Leu variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV001876023	SCV004844960	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2023-12-01	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant is located in the C-terminal CM1 domain of the PCSK9 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 3/239136 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.