Submissions for variant NM_174936.4(PCSK9):c.1069C>T (p.Arg357Cys)

gnomAD frequency: 0.00012  dbSNP: rs148562777

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698070	SCV000826711	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2022-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 357 of the PCSK9 protein (p.Arg357Cys). This variant is present in population databases (rs148562777, gnomAD 0.04%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 29127338, 30270359, 33418990). ClinVar contains an entry for this variant (Variation ID: 575758). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects PCSK9 function (PMID: 29127338). 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.
Color Diagnostics, LLC DBA Color Health	RCV000776498	SCV000912080	uncertain significance	Familial hypercholesterolemia	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 357 of the PCSK9 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An invitro functional study has shown that this variant causes higher binding affinity for LDLR and results in reduced LDL uptake activity compared to wildtype (PMID: 29127338). This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 33418990, 34297352, Fairoozy 2018, dissertation, University College London). One of these individuals also carried a pathogenic variant in the same gene that could explain the observed phenotype (PMID: 33418990). This variant has been identified in 41/282766 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001097585	SCV001253875	uncertain significance	Hypobetalipoproteinemia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000698070	SCV001253876	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000698070	SCV001653672	likely pathogenic	Hypercholesterolemia, autosomal dominant, 3	2021-05-24	criteria provided, single submitter	clinical testing	Gain of function according to functional studies PMID:29127338
GeneDx	RCV001585641	SCV001819180	uncertain significance	not provided	2024-11-14	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect with reduced LDL uptake compared to lid type protein (rDi Taranto et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25904937, 29127338, 16211558, 34426522, 30270359, 33173529, 33258288, 33418990, 34297352, 35928446, 29802317, 37443404)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001585641	SCV002009422	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV001585641	SCV002503226	uncertain significance	not provided	2022-02-15	criteria provided, single submitter	clinical testing
Mendelics	RCV002249415	SCV002518458	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Arcensus	RCV000698070	SCV002564548	likely pathogenic	Hypercholesterolemia, autosomal dominant, 3	2013-02-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001585641	SCV004700886	likely pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	PCSK9: PM1, PS4:Moderate, PM2:Supporting, PP3, PS3:Supporting
All of Us Research Program, National Institutes of Health	RCV000698070	SCV004836452	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 357 of the PCSK9 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An invitro functional study has shown that this variant causes higher binding affinity for LDLR and results in reduced LDL uptake activity compared to wildtype (PMID: 29127338). This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 33418990, 34297352, Fairoozy 2018, dissertation, University College London). One of these individuals also carried a pathogenic variant in the same gene that could explain the observed phenotype (PMID: 33418990). This variant has been identified in 41/282766 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002249415	SCV005184501	uncertain significance	not specified	2024-05-28	criteria provided, single submitter	clinical testing	Variant summary: PCSK9 c.1069C>T (p.Arg357Cys) results in a non-conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251372 control chromosomes. The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05). c.1069C>T has been reported in the literature in individuals affected with Hypercholesterolemia, as also been identified as an incidental finding in an individual with metabolic disease, and has been reported in a newborn receiving newborn screening, without primary information to analyze (Costa Quaio_2020, Di Taranto_2017, Meshkov_2021, Vic Shum_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in increased PCSK9 activities in HEK293 cells (Di Taranto_2017). The following publications have been ascertained in the context of this evaluation (PMID: 33258288, 34297352, 33418990, 37443404). ClinVar contains an entry for this variant (Variation ID: 575758). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004535739	SCV004722998	uncertain significance	PCSK9-related disorder	2024-02-27	no assertion criteria provided	clinical testing	The PCSK9 c.1069C>T variant is predicted to result in the amino acid substitution p.Arg357Cys. This variant was reported in individuals with hypercholesterolaemia (Di Taranto et al 2017. PubMed ID: 29127338; Meshkov A et al 2021. PubMed ID: 33418990). In vitro functional studies suggest this variant leads to a gain of function in the NARC1 protein that results in increased degradation of LDLR and consequently higher levels of LDL in the blood, which may present as familial hypercholesteremia (Di Taranto et al. 2017. PubMed ID: 29127338). This variant results in an amino acid change within the conserved catalytic site of the NARC1 protein (Allard et al. 2005. PubMed ID: 16211558; Di Taranto et al. 2017. PubMed ID: 29127338). A similar variant that results in the amino acid change p.Arg357His has also been reported in patients with hypercholesterolaemia (Allard et al. 2005. PubMed ID: 16211558). This variant is reported in 0.039% of alleles in individuals of South Asian descent in gnomAD, which may be too common to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain.