Submissions for variant NM_174936.4(PCSK9):c.45GCT[9] (p.Leu22_Leu23dup)

dbSNP: rs35574083

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000256321	SCV000323027	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/100 French Canadian and 0/100 French normolipidemic and trigliceridemic controls; 0/100 Tunisian normolipidemic individuals
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081155	SCV000555874	benign	Hypercholesterolemia, autosomal dominant, 3	2025-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000484438	SCV000572390	likely benign	not specified	2018-02-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health	RCV000256321	SCV000690982	likely benign	Hypercholesterolemia, familial, 1	2017-07-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590072	SCV000699999	benign	not provided	2016-10-12	criteria provided, single submitter	clinical testing	Variant summary: The PCSK9 c.60_65dupGCTGCT (p.Leu20_Leu21dup) variant involves the duplication of 6 nucleotides in a Leucine repeat region, changing 9 Leucines to 11 Leucines. Mutation taster predicts a benign outcome for this variant. This variant was found in 49/22348 control chromosomes (1 homozygote) at a frequency of 0.0021926, which is approximately 23 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.0000938), suggesting this variant is likely a benign polymorphism. This variant has been reported in families with FH and FCHL but did not clearly cosegregate with disease. Additionally, the variant has been reported in patients that carry other pathogenic variants which would suggest that this is a benign variant. Taken together, this variant is classified as benign.
Robarts Research Institute, Western University	RCV000256321	SCV000782987	likely benign	Hypercholesterolemia, familial, 1	2018-01-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776036	SCV000910635	likely benign	Familial hypercholesterolemia	2018-06-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590072	SCV001470594	benign	not provided	2020-07-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002356357	SCV002656171	likely benign	Cardiovascular phenotype	2018-07-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000590072	SCV002821399	benign	not provided	2025-02-01	criteria provided, single submitter	clinical testing	PCSK9: BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590072	SCV003799483	likely benign	not provided	2023-10-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000484438	SCV004848596	benign	not specified	2021-11-05	criteria provided, single submitter	clinical testing	The p.Leu22_Leu23dup variant in PCSK9 is classified as benign because it has been identified in 0.74% (65/8730) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000256321	SCV000606671	benign	Hypercholesterolemia, familial, 1		no assertion criteria provided	research