Submissions for variant NM_000527.5(LDLR):c.661G>T (p.Asp221Tyr)

dbSNP: rs875989906

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000237890	SCV002568107	pathogenic	Hypercholesterolemia, familial, 1	2022-06-01	reviewed by expert panel	curation	NM_000527.5(LDLR):c.661G>T (p.Asp221Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PS3, PM1, PM2, PS4_Moderate, PP3 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: PP1_Strong - Variant segregates with phenotype in 7 informative meiosis in at least 4 families from different labs (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière)): 6 affected family members have the variant and 1 non-affected family members do not have the variant. PS3 - PMID: 34167030 - Level 1 assay - Heterologous cells (CHO), FACS: Normal cell surface LDLR, 5% LDL-LDLR binding and 8% uptake. PM1 - Missense at codon 221. PM2 is Met and it is exon 4. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PS4_moderate - Variant meets PM2. Variant identified in 9 unrelated index cases (1 case with Simon-Broome published in PMID 32331935; 2 cases with Simon Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN/Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière). PP3 - REVEL = 0.978. PP4 - Variant meets PM2. Variant identified in 9 unrelated index cases (1 case with Simon-Broome published in PMID 32331935; 2 cases with Simon Broome criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN/Simon Broome criteria from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).
LDLR-LOVD, British Heart Foundation	RCV000237890	SCV000294861	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	research
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237890	SCV000322907	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/190 non-FH alleles; 0/50 normolipidemic individuals
Fundacion Hipercolesterolemia Familiar	RCV000237890	SCV000607480	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV001050137	SCV001214231	pathogenic	Familial hypercholesterolemia	2019-03-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp221 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15523646,23375686, 11196104, 15241806, 220236128, 2698793, 25461735). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to segregate with familial hypercholesterolemia in a family (PMID: 9237502) and has been observed in individuals affected with this condition (PMID: 7649546, 7573037, 23375686, 10206683, 17765246, Invitae). This variant is also known as D200Y in the literature.  ClinVar contains an entry for this variant (Variation ID: 251356). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 221 of the LDLR protein (p.Asp221Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000237890	SCV001428968	pathogenic	Hypercholesterolemia, familial, 1	2017-08-23	criteria provided, single submitter	clinical testing