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.2446A>C (p.Lys816Gln)

CA404098844

440697 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 8b2fda49-2957-482c-985e-3acbe1cc2fc4

HGVS expressions

NM_000527.5:c.2446A>C

NM_000527.5(LDLR):c.2446A>C (p.Lys816Gln)

NC_000019.10:g.11129569A>C

CM000681.2:g.11129569A>C

NC_000019.9:g.11240245A>C

CM000681.1:g.11240245A>C

NC_000019.8:g.11101245A>C

NG_009060.1:g.45189A>C

ENST00000558518.6:c.2446A>C

ENST00000252444.9:n.2700A>C

ENST00000455727.6:c.1942A>C

ENST00000535915.5:c.2323A>C

ENST00000545707.5:c.1912A>C

ENST00000557933.5:c.2508A>C

ENST00000558013.5:c.2446A>C

ENST00000558518.5:c.2446A>C

ENST00000560628.1:n.108+1915A>C

NM_000527.4:c.2446A>C

NM_001195798.1:c.2446A>C

NM_001195799.1:c.2323A>C

NM_001195800.1:c.1942A>C

NM_001195803.1:c.1912A>C

NM_001195798.2:c.2446A>C

NM_001195799.2:c.2323A>C

NM_001195800.2:c.1942A>C

NM_001195803.2:c.1912A>C

Uncertain Significance

PM2

PS1 PVS1 PP3 BA1 BS1 PM5 BP4

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR): c.2446A>C (p.Lys816Gln) variant is classified as Uncertain significance - insufficient evidence, for Familial Hypercholesterolemia by applying evidence code PM2 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 from gnomAD (gnomAD v2.1.1)

PM2

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

PS1

2 other missense variants in the same codon: . NM_000527.5(LDLR):c.2447A>G (p.Lys816Arg) (ClinVar ID 440698) Conflicting interpretations of pathogenicity by these guidelines . NM_000527.5(LDLR):c.2447A>G (p.Lys816Arg) (ClinVar ID 1791406) Uncertain significance by these guidelines There are no variant in the same codon classified as Pathogenic by these guidelines.

PVS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP3

REVEL = 0.552. It is not above 0.75, splicing evaluation needed. Functional data on splicing not available. A) variant is not on limits B) Variant does not create GT C) There is an AG nearby: . MES scores: wt cryptic= -5.82, variant cryptic= -1.26, canonical acceptor= 8.21. . MES scores: wt cryptic= -4.18, variant cryptic= -2.41, canonical acceptor= 8.21. Variant is not predicted to affect splicing.

BA1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

BS1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM5

BP4

REVEL = 0.552. It is not below 0.5, splicing evaluation needed. Functional data on splicing not available. A) variant is not on limits B) Variant does not create GT Variant is not predicted to affect splicing.

Approved on: 2023-04-28

Published on: 2023-04-28

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