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]

Link to SEPIO compliant JSON-LD document

Variant: NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro)

CA10576302

226352 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: a4cb57c2-99f7-4f49-9061-443b0d7a8f88

HGVS expressions

NM_000527.5:c.1217G>C

NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro)

NC_000019.10:g.11113308G>C

CM000681.2:g.11113308G>C

NC_000019.9:g.11223984G>C

CM000681.1:g.11223984G>C

NC_000019.8:g.11084984G>C

NG_009060.1:g.28928G>C

ENST00000558518.6:c.1217G>C

ENST00000252444.9:n.1471G>C

ENST00000455727.6:c.713G>C

ENST00000535915.5:c.1094G>C

ENST00000545707.5:c.836G>C

ENST00000557933.5:c.1217G>C

ENST00000558013.5:c.1217G>C

ENST00000558518.5:c.1217G>C

ENST00000560173.1:n.216G>C

ENST00000560467.1:n.697G>C

NM_000527.4:c.1217G>C

NM_001195798.1:c.1217G>C

NM_001195799.1:c.1094G>C

NM_001195800.1:c.713G>C

NM_001195803.1:c.836G>C

NM_001195798.2:c.1217G>C

NM_001195799.2:c.1094G>C

NM_001195800.2:c.713G>C

NM_001195803.2:c.836G>C

Likely Pathogenic

PP1 PP4 PP3 PM2 PM5 PS4_Supporting

PS2 PS3 PS1 PM6 PM3 PM1 PM4 BA1 BS2 PVS1 BS4 BS3 BS1 BP7 BP2 BP4

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):c1217G>C (p.Arg406Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PM5, PS4_Supporting, PP1, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.89, which is above the threshold of 0.75. PM5 - 2 other missense variants in the same codon: 1) NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) – Likely pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1217G>C (p.Arg406Trp) – Pathogenic by these guidelines. There is 1 variant in the same codon classified as Pathogenic by these guidelines. – therefore PM5 is met. PS4_Supporting - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (1 case with SB criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation– FH VCEP member lab; 1 case with DLCN criteria from PMID: 16250003) PP1 - Variant segregates with phenotype in 2 informative meioses from 2 families in data provided by FH VCEP member labs (Laboratory of Genetics and Molecular Cardiology – 1 family: 1 affected family member with the variant; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation – 1 family: 1 affected family member with the variant). PP4 - Variant meets PM2. Identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.

PP1

Variant segregates with phenotype in 2 informative meioses from 2 families in data provided by FH VCEP member labs (Laboratory of Genetics and Molecular Cardiology – 1 family: 1 affected family member with the variant; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation – 1 family: 1 affected family member with the variant).

PP4

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

PP3

REVEL = 0.89

PM2

This variant is absent from gnomAD (gnomAD v2.1.1).

PM5

2 other missense variants in the same codon: 1) NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) – Likely pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1217G>C (p.Arg406Trp) – Pathogenic by these guidelines - therefore PM5 is met.

PS4_Supporting

Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (1 case with SB criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation– FH VCEP member lab; 1 case with DLCN criteria from PMID: 16250003).

PS2