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.2479G>A (p.Val827Ile)

CA023677

36462 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7013887c-0f2d-4f01-93b1-32e2c36dc390

HGVS expressions

NM_000527.5:c.2479G>A

NM_000527.5(LDLR):c.2479G>A (p.Val827Ile)

NC_000019.10:g.11129602G>A

CM000681.2:g.11129602G>A

NC_000019.9:g.11240278G>A

CM000681.1:g.11240278G>A

NC_000019.8:g.11101278G>A

NG_009060.1:g.45222G>A

ENST00000558518.6:c.2479G>A

ENST00000252444.9:n.2733G>A

ENST00000455727.6:c.1975G>A

ENST00000535915.5:c.2356G>A

ENST00000545707.5:c.1945G>A

ENST00000557933.5:c.2541G>A

ENST00000558013.5:c.2479G>A

ENST00000558518.5:c.2479G>A

ENST00000560628.1:n.108+1948G>A

NM_000527.4:c.2479G>A

NM_001195798.1:c.2479G>A

NM_001195799.1:c.2356G>A

NM_001195800.1:c.1975G>A

NM_001195803.1:c.1945G>A

NM_001195798.2:c.2479G>A

NM_001195799.2:c.2356G>A

NM_001195800.2:c.1975G>A

NM_001195803.2:c.1945G>A

Uncertain Significance

PP1 PP3

PP4 PP2 BA1 PVS1 PM6 PM2 PM3 PM1 PM4 PM5 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PS2 PS4 PS3 PS1

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

NM_000527.5(LDLR):c.2479G>A (p.Val827Ile) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1 and PP3) 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: PP1 - Variant segregates with FH phenotype in 3 informative meiosis from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). PP3 - REVEL: 0,771. Score is above 0,75.

PP1

Variant segregates with FH phenotype in 3 informative meiosis from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation).

PP3

REVEL: 0,771. Score is above 0,75.

PP4

PM2 is not met. Not applicable.

PP2

Not applicable.

BA1

FAF = 0.0007719 (0.08%) in Latino exomes (gnomAD v2.1.1). FAF is not above 0.5%.

PVS1

Missense variant. Not applicable.

PM6

No de novo cases were identified.

PM2

PopMax MAF = 0.01649 (1.65%) in Ashkenazi Jewish exomes (gnomAD v2.1.1). MAF is not below 0.02%.

PM3

PM2 is not met. Not applicable.

PM1

Missense at codon 827 - it is not exon 4 or any of the 60 Cys residues listed. Not applicable.

PM4

Missense variant. Not applicable.

PM5

No other missense variants classified as Pathogenic by these guidelines. Two missense variants described in the same codon (accessed 19 August 2020): (1)NM_000527.4(LDLR):c.2479G>T (p.Val827Phe) (ClinVar ID 375840) - VUS by these guidelines. (2)NM_000527.5(LDLR):c.2480T>A (p.Val827Asp) (ClinVar ID 963080) - VUS by these guidelines.

BS2

Two unaffected heterozygous carriers from Molecular Genetics Laboratory (Centre for Cardiovascular Surgery and Transplantation). At least 3 htz unaffected carriers are needed for adding this point. BS2 not met.

BS4

insuficient information

BS3

No functional assays performed/found - not applicable.

BS1

FAF = 0.0007719 (0.08%) in Latino exomes (gnomAD v2.1.1). FAF is not above 0.2%.

BP5

Not applicable.

BP7

Missense variant. Not applicable.

BP2

Not applicable.

BP3

Not applicable.

BP4

REVEL: 0,771. Score is not below 0,15.

BP1

Not applicable.

PS2

No de novo cases were identified.

PS4

PM2 is not met. Not applicable.

PS3

No functional assays performed/found - not applicable.

PS1

No variant described that leads to the same amino acid change.

Approved on: 2021-06-22

Published on: 2021-06-24

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