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]

Variant: NM_000527.5(LDLR):c.2T>C (p.Met1Thr)

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CA404071092

441174 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7f40ca33-9ff0-4ff1-93fb-6c6a4b1bd789

Approved on: 2022-04-22

Published on: 2022-04-22

HGVS expressions

NM_000527.5:c.2T>C

NM_000527.5(LDLR):c.2T>C (p.Met1Thr)

NC_000019.10:g.11089550T>C

CM000681.2:g.11089550T>C

NC_000019.9:g.11200226T>C

CM000681.1:g.11200226T>C

NC_000019.8:g.11061226T>C

NG_009060.1:g.5170T>C

ENST00000558518.6:c.2T>C

ENST00000455727.6:c.2T>C

ENST00000535915.5:c.2T>C

ENST00000545707.5:c.2T>C

ENST00000557933.5:c.2T>C

ENST00000557958.1:n.88T>C

ENST00000558013.5:c.2T>C

ENST00000558518.5:c.2T>C

ENST00000560502.5:n.88T>C

NM_000527.4:c.2T>C

NM_001195798.1:c.2T>C

NM_001195799.1:c.2T>C

NM_001195800.1:c.2T>C

NM_001195803.1:c.2T>C

NM_001195798.2:c.2T>C

NM_001195799.2:c.2T>C

NM_001195800.2:c.2T>C

NM_001195803.2:c.2T>C

NR_163945.1:n.110A>G

Likely Pathogenic

PVS1_Moderate PM2 PM5

BP7 BP4 PS1 PS3 PP4 PP3 PM4 BA1 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.2T>C (p.Met1Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PVS1_Moderate, and PM5 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. 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_000527.5(LDLR):c.1A>G (p.Met1Val) - 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.

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_000527.5(LDLR):c.1A>G (p.Met1Val) - 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.

BP7