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

Approved on: 2022-04-22

Published on: 2022-04-22

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

PVS1_Moderate PS4_Supporting PP4 PM2 PM5

BS3 BS1 BP7 BP4 PS3 PP3 BA1 PM4

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.

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.

PM2

Variant is absent from gnomAD (v2.1.1).

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.

BS3