Submissions for variant NM_000527.5(LDLR):c.1942T>C (p.Ser648Pro)

dbSNP: rs879255079

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237722	SCV004022446	likely pathogenic	Hypercholesterolemia, familial, 1	2023-04-28	reviewed by expert panel	curation	The NM_000527.5(LDLR):c.1942T>C (p.Ser648Pro) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PS3, PM2 and PP4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3 - 2 Level 1 assays: PMID 25386756: Heterologous cells (CHO), FACS assays - result - 50% cell surface LDLR and binding and 26% uptake. PMID 23021490: Heterologous cells (CHO), 125I-LDL and WB assays - result - 30-50% LDLR activity; reduced mature protein. ---- activity is below 70% of wild-type, so functional studies are consistent with damaging effect and PS3 is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PP4 - Variant meets PM2 and is identified in 1 index cases who fulfills SB possible criteria for FH from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so PP4 is met.
LDLR-LOVD, British Heart Foundation	RCV000237722	SCV000295762	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237722	SCV000322990	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/200 non-FH alleles
GeneDx	RCV002461042	SCV002757358	likely pathogenic	not provided	2022-05-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as expression in transfected cell lines is significantly reduced (Etxebarria A et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as S627P using alternate nomenclature in an individual with familial hypercholesterolemia (Bourbon M et al., 2008); This variant is associated with the following publications: (PMID: 23021490, 25386756, 17765246)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235162	SCV003934620	likely pathogenic	Familial hypercholesterolemia	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1942T>C (p.Ser648Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251468 control chromosomes (gnomAD). c.1942T>C has been reported in the literature in at least one individual affected with Hypercholesterolemia (Bourbon_2008). At least two publications reports experimental evidence evaluating an impact on protein function, finding substantially decreased mature LDLR protein and impaired uptake and degredation of LDL (Silva_2012, Etxebarria_2014). The following publications have been ascertained in the context of this evaluation (PMID: 17765246, 23021490, 25386756). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.