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]

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Variant: NM_000527.5(LDLR):c.1158C>G (p.Asp386Glu)

CA10585332

251693 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: c572d76d-1ce5-4e0c-bdb4-135f13d6e2c5

HGVS expressions

NM_000527.5:c.1158C>G

NM_000527.5(LDLR):c.1158C>G (p.Asp386Glu)

NC_000019.10:g.11111611C>G

CM000681.2:g.11111611C>G

NC_000019.9:g.11222287C>G

CM000681.1:g.11222287C>G

NC_000019.8:g.11083287C>G

NG_009060.1:g.27231C>G

ENST00000558518.6:c.1158C>G

ENST00000252444.9:n.1412C>G

ENST00000455727.6:c.654C>G

ENST00000535915.5:c.1035C>G

ENST00000545707.5:c.777C>G

ENST00000557933.5:c.1158C>G

ENST00000558013.5:c.1158C>G

ENST00000558518.5:c.1158C>G

ENST00000560173.1:n.157C>G

ENST00000560467.1:n.638C>G

NM_000527.4:c.1158C>G

NM_001195798.1:c.1158C>G

NM_001195799.1:c.1035C>G

NM_001195800.1:c.654C>G

NM_001195803.1:c.777C>G

NM_001195798.2:c.1158C>G

NM_001195799.2:c.1035C>G

NM_001195800.2:c.654C>G

NM_001195803.2:c.777C>G

Uncertain Significance

PP4 PM2

BP2 PS3 PP3 PM5

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.1158C>G (p.Asp386Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, 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: This variant is absent in gnomAD (gnomAD v2.1.1). PP4: This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).

PP4

This variant meets PM2 and is identified in 1 index case who met clinical criteria for FH after alternative causes for high cholesterol were excluded (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).

PM2

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

BP2

Variant found in a HeFH phenotype, but a proven pathogenic variant in LDLR c.1150C>T (p.Gln384*) is already present. Two variant are suspected to be in trans but not confirmed (Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies , APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière).

PS3

Functional data is not available.

PP3

REVEL score = 0.637, it is not above 0.75, functional data on splicing is not available, splicing prediction required. The variant is out of limit creating de novo accept site, and does not creating de novo donor site. Variant is not predicted to alter splicing.

PM5

There is one other variant in the same codon: LDLR: NM_000527:c.1156G>T (p.Asp386Tyr) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.

Approved on: 2022-03-25

Published on: 2022-04-25

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