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>G (p.Met1Val)

CA10584719

250967 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: cd1316c6-5809-4352-a9ab-972c568d022d

HGVS expressions

NM_000527.5:c.1A>G

NM_000527.5(LDLR):c.1A>G (p.Met1Val)

NC_000019.10:g.11089549A>G

CM000681.2:g.11089549A>G

NC_000019.9:g.11200225A>G

CM000681.1:g.11200225A>G

NC_000019.8:g.11061225A>G

NG_009060.1:g.5169A>G

ENST00000558518.6:c.1A>G

ENST00000455727.6:c.1A>G

ENST00000535915.5:c.1A>G

ENST00000545707.5:c.1A>G

ENST00000557933.5:c.1A>G

ENST00000557958.1:n.87A>G

ENST00000558013.5:c.1A>G

ENST00000558518.5:c.1A>G

ENST00000560502.5:n.87A>G

NM_000527.4:c.1A>G

NM_001195798.1:c.1A>G

NM_001195799.1:c.1A>G

NM_001195800.1:c.1A>G

NM_001195803.1:c.1A>G

NM_001195798.2:c.1A>G

NM_001195799.2:c.1A>G

NM_001195800.2:c.1A>G

NM_001195803.2:c.1A>G

NR_163945.1:n.111T>C

Likely Pathogenic

PP4 PVS1_Moderate PM5 PM2 PS4_Supporting

PS3 BP4 BP7 BA1 PP3 PM4 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>G (p.Met1Val) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes as PM2, PVS1_Moderate, PM5, PS4_Supporting, 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. PS4_Supporting – variant meets PM2 and is identified in 3 unrelated index cases who fulfill clinical criteria for FH (3 cases with SB criteria from PMID: 11462246). PP4 - variant meets PM2 and is identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PM5 - four other missense variants at this same codon have been reported, and one is Pathogenic: 1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – 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.

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

Variant is predicted to affect the initiation codon.

PM5

Four other missense variants at this same codon have been reported, and one is Pathogenic: 1) NM_000527.5(LDLR):c.1A>C (p.Met1Leu) – 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.

PM2

Variant is absent from gnomAD (v2.1.1).

PS4_Supporting

Variant meets PM2 and is identified in 3 unrelated index cases who fulfill clinical criteria for FH (3 cases with SB criteria from PMID: 11462246).

PS3