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.1A>C (p.Met1Leu)

CA10584718

250966 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: e7450868-fc21-439a-949f-f84feae9c98d

HGVS expressions

NM_000527.5:c.1A>C

NM_000527.5(LDLR):c.1A>C (p.Met1Leu)

NC_000019.10:g.11089549A>C

CM000681.2:g.11089549A>C

NC_000019.9:g.11200225A>C

CM000681.1:g.11200225A>C

NC_000019.8:g.11061225A>C

NG_009060.1:g.5169A>C

ENST00000558518.6:c.1A>C

ENST00000455727.6:c.1A>C

ENST00000535915.5:c.1A>C

ENST00000545707.5:c.1A>C

ENST00000557933.5:c.1A>C

ENST00000557958.1:n.87A>C

ENST00000558013.5:c.1A>C

ENST00000558518.5:c.1A>C

ENST00000560502.5:n.87A>C

NM_000527.4:c.1A>C

NM_001195798.1:c.1A>C

NM_001195799.1:c.1A>C

NM_001195800.1:c.1A>C

NM_001195803.1:c.1A>C

NM_001195798.2:c.1A>C

NM_001195799.2:c.1A>C

NM_001195800.2:c.1A>C

NM_001195803.2:c.1A>C

NR_163945.1:n.111T>G

Pathogenic

PS3 PP1_Moderate PP4 PVS1_Moderate PM2 PS4_Supporting

PS1 PS2 BP2 BP4 BP7 BA1 PP3 PM5 PM3 PM4 PM6 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.1A>C (p.Met1Leu) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes as PM2, PVS1_Moderate, PS3, PS4_Supporting, PP1_Moderate, 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 - variant is absent from gnomAD (v2.1.1). PVS1_Moderate – variant is predicted to affect the initiation codon. PS3 - Level 1 functional studies performed - Heterologous cells (CHO), FACS: results of 60% cell surface LDLR, 59% LDL binding and 66% LDL uptake, compared to wild-type. Note - Level 3 luciferase reporter assays were also performed: results of 5% luciferase construct activity compared to wild-type. Both studies performed in PMID: 34572405. PS4_Supporting - variant meets PM2 and is identified in 4 unrelated index cases who fulfill clinical criteria for FH (4 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – FH VCEP member lab). PP1_Moderate – variant segregates with phenotype in 4 informative meioses in 3 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 3 families: 4 affected relatives with 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. Note: four other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.1A>G (p.Met1Val) – Likely pathogenic by these guidelines. 2) NM_000527.4(LDLR):c.2T>C (p.Met1Thr) - Likely pathogenic by these guidelines. 3) NM_000527.4(LDLR):c.3G>A (p.Met1Ile) - Likely pathogenic by these guidelines. 4) NM_000527.5(LDLR):c.3G>T (p.Met1Ile) - Likely pathogenic by these guidelines. -PM5 not applicable as such variants must be Pathogenic.

PS3

Level 1 functional studies performed - Heterologous cells (CHO), FACS: results of 60% cell surface LDLR, 59% LDL binding and 66% LDL uptake, compared to wild-type. Note - Level 3 luciferase reporter assays were also performed: results of 5% luciferase construct activity compared to wild-type. Both studies performed in PMID: 34572405.

PP1_Moderate

Variant segregates with phenotype in 4 informative meioses in 3 families (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 3 families: 4 relatives affected with 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.

PVS1_Moderate

This variant is predicted to affect the initiation codon.

PM2

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

PS4_Supporting

Variant meets PM2 and is identified in 4 unrelated index cases who fulfill clinical criteria for FH (4 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – FH VCEP member lab).

PS1