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.796G>T (p.Asp266Tyr)

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CA10585134

251456 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 02855998-6cea-4d61-ab76-99c4e0737e92

Approved on: 2022-05-05

Published on: 2022-06-30

HGVS expressions

NM_000527.5:c.796G>T

NM_000527.5(LDLR):c.796G>T (p.Asp266Tyr)

NC_000019.10:g.11106666G>T

CM000681.2:g.11106666G>T

NC_000019.9:g.11217342G>T

CM000681.1:g.11217342G>T

NC_000019.8:g.11078342G>T

NG_009060.1:g.22286G>T

ENST00000558518.6:c.796G>T

ENST00000252444.9:n.1050G>T

ENST00000455727.6:c.314-726G>T

ENST00000535915.5:c.673G>T

ENST00000545707.5:c.415G>T

ENST00000557933.5:c.796G>T

ENST00000558013.5:c.796G>T

ENST00000558518.5:c.796G>T

ENST00000558528.1:n.311G>T

ENST00000560467.1:n.396G>T

NM_000527.4:c.796G>T

NM_001195798.1:c.796G>T

NM_001195799.1:c.673G>T

NM_001195800.1:c.314-726G>T

NM_001195803.1:c.415G>T

NM_001195798.2:c.796G>T

NM_001195799.2:c.673G>T

NM_001195800.2:c.314-726G>T

NM_001195803.2:c.415G>T

Pathogenic

PM5_Strong PP4 PP3 PP1_Moderate PM2

BP3 BP2 BP4 BP1 BP7 BP5 BA1 PS2 PS4 PS3 PS1 PP2 PM6 PM4 PM3 PM1 BS2 PVS1 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.796G>T (p.Asp266Tyr) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM5_Strong, PM2, PP1_Moderate, PP3 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: PM5_Strong - 4 other missense variants in the same codon: - NM_000527.5(LDLR): c.796G>T (p.Asp266Asn) (ClinVar ID 226334) - Pathogenic by these guidelines, - NM_000527.5(LDLR): c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely pathogenic by these guidelines, - NM_000527.5(LDLR): c.797A>G (p.Asp266Gly) (ClinVar ID 251457) - Likely pathogenic by these guidelines, - NM_000527.5(LDLR): c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines. There are 2 variants in the same codon classified as Pathogenic by these guidelines; PM2 - This variant is absent from gnomAD (gnomAD v2.1.1); PP1_Moderate - 5 informative meioses published in PMID 11196104. PP3 – REVEL = 0.97; PP4 - Variant meets PM2. Identified in 1 FH case fulfilling MEDPED criteria published in PMID 11196104.

PM5_Strong

4 other missense variants in the same codon: - NM_000527.5(LDLR): c.796G>T (p.Asp266Asn) (ClinVar ID 226334) - Pathogenic by these guidelines, - NM_000527.5(LDLR): c.797A>T (p.Asp266Val) (ClinVar ID 251458) - Likely pathogenic by these guidelines, - NM_000527.5(LDLR): c.797A>G (p.Asp266Gly) (ClinVar ID 251457) - Likely pathogenic by these guidelines, - NM_000527.5(LDLR): c.798T>A (p.Asp266Glu) - (ClinVar ID 161287) - Pathogenic by these guidelines. There are 2 variants in the same codon classified as Pathogenic by these guidelines.

PP4

Variant meets PM2. Identified in 1 FH case fulfilling MEDPED criteria published in PMID 11196104.

PP3

REVEL = 0.97

PP1_Moderate

5 informative meioses published in PMID 11196104

PM2

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

BP3