Evidence Repository - Clinical Genome Resources

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.551G>A (p.Cys184Tyr)

CA023721

3739 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 2f05ce00-876a-478f-b36c-26dfc18742c8

HGVS expressions

NM_000527.5:c.551G>A

NM_000527.5(LDLR):c.551G>A (p.Cys184Tyr)

NC_000019.10:g.11105457G>A

CM000681.2:g.11105457G>A

NC_000019.9:g.11216133G>A

CM000681.1:g.11216133G>A

NC_000019.8:g.11077133G>A

NG_009060.1:g.21077G>A

ENST00000558518.6:c.551G>A

ENST00000252444.9:n.805G>A

ENST00000455727.6:c.314-1935G>A

ENST00000535915.5:c.428G>A

ENST00000545707.5:c.314-1108G>A

ENST00000557933.5:c.551G>A

ENST00000558013.5:c.551G>A

ENST00000558518.5:c.551G>A

ENST00000560467.1:n.151G>A

NM_000527.4:c.551G>A

NM_001195798.1:c.551G>A

NM_001195799.1:c.428G>A

NM_001195800.1:c.314-1935G>A

NM_001195803.1:c.314-1108G>A

NM_001195798.2:c.551G>A

NM_001195799.2:c.428G>A

NM_001195800.2:c.314-1935G>A

NM_001195803.2:c.314-1108G>A

Pathogenic

PS4 PS3 PP4 PM2 PM1 PP1_Strong

PS2 PM6 BA1 BS4 BS3 BS1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.551G>A (p.Cys184Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PM1, PS3, PS4, PP1_Strong, 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: PM2 - PopMax MAF = 0.00019 (0.019%) in European Non-Finnish genomes (gnomAD v2.1.1). PP3 - REVEL = 0.85, which is above the threshold of 0.75. PM1 - variant meets PM2 and is located in exon 4. PS3 - Level 1 functional studies performed - Heterologous cells (CHO), FACS: Result of normal cell surface LDLR (100%), 4% LDL binding and 18% LDL uptake, compared to wild-type (PMID: 34167030). PS4 - Variant meets PM2 and is identified in at least 22 unrelated index cases who fulfill clinical criteria for FH (8 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN criteria from Robarts Research Institute; 5 cases with DLCN criteria from PathWest Laboratory Medicine WA; 2 cases with DLCN criteria from Color; 1 case with MEDPED criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory). PP1_Strong - Variant segregates with phenotype in 14 informative meioses from 8 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 4 families: 8 relatives affected with the variant and 1 relative unaffected without the variant; Robarts Research Institute – 2 families: 2 relatives affected with the variant; PathWest Laboratory Medicine WA – 2 families: 2 affected relative with the variant and 1 unaffected relative without the variant) PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.

PS4

Variant meets PM2 and is identified in at least 22 unrelated index cases who fulfill clinical criteria for FH (8 cases with SB criteria from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge; 6 cases with DLCN criteria from Robarts Research Institute; 5 cases with DLCN criteria from PathWest Laboratory Medicine WA; 2 cases with DLCN criteria from Color; 1 case with MEDPED criteria from Mayo Clinic Atherosclerosis and Lipid Genomics Laboratory).

PS3

Level 1 functional studies performed - Heterologous cells (CHO), FACS: Result of normal cell surface LDLR (100%), 4% LDL binding and 18% LDL uptake, compared to wild-type (PMID: 34167030).

PP4

Variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.

PM2

PopMax MAF = 0.00019 (0.019%) in European Non-Finnish genomes (gnomAD v2.1.1).

PM1

Variant meets PM2 and is located in exon 4.

PP1_Strong

Variant segregates with phenotype in 14 informative meioses from 8 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 4 families: 8 relatives affected with the variant and 1 relative unaffected without the variant; Robarts Research Institute – 2 families: 2 relatives affected with the variant; PathWest Laboratory Medicine WA – 2 families: 2 affected relative with the variant and 1 unaffected relative without the variant)

PS2