Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000527.5(LDLR):c.661G>T (p.Asp221Tyr)

CA10585046

251356 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 0c078f82-bf62-4550-a36c-aa3db8e89b02

HGVS expressions

NM_000527.5:c.661G>T
NM_000527.5(LDLR):c.661G>T (p.Asp221Tyr)
NC_000019.10:g.11105567G>T
CM000681.2:g.11105567G>T
NC_000019.9:g.11216243G>T
CM000681.1:g.11216243G>T
NC_000019.8:g.11077243G>T
NG_009060.1:g.21187G>T
ENST00000558518.6:c.661G>T
ENST00000252444.9:n.915G>T
ENST00000455727.6:c.314-1825G>T
ENST00000535915.5:c.538G>T
ENST00000545707.5:c.314-998G>T
ENST00000557933.5:c.661G>T
ENST00000558013.5:c.661G>T
ENST00000558518.5:c.661G>T
ENST00000560467.1:n.261G>T
NM_000527.4:c.661G>T
NM_001195798.1:c.661G>T
NM_001195799.1:c.538G>T
NM_001195800.1:c.314-1825G>T
NM_001195803.1:c.314-998G>T
NM_001195798.2:c.661G>T
NM_001195799.2:c.538G>T
NM_001195800.2:c.314-1825G>T
NM_001195803.2:c.314-998G>T

Pathogenic

Met criteria codes 7
PS4_Moderate PS3 PP4 PP3 PP1_Strong PM2 PM1
Not Met criteria codes 19
BS4 BS3 BS1 BS2 BP5 BP7 BP2 BP3 BP4 BP1 PVS1 PS2 PS1 PP2 PM6 PM3 PM4 PM5 BA1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
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).
Met criteria codes
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).
PS3
PMID: 34167030 - Level 1 assay - Heterologous cells (CHO), FACS: Normal cell surface LDLR, 5% LDL-LDLR binding and 8% uptake.
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).
PP3
REVEL = 0.978
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.
PM2
This variant is absent from gnomAD (gnomAD v2.1.1)
PM1
Missense at codon 221. PM2 is Met and it is exon 4
Not Met criteria codes
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
PM1 is met, PM5 is not applicable
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2022-06-01
Published on: 2022-06-30
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