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.343C>T (p.Arg115Cys)

CA043225

251162 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 6663dc62-0d62-4323-967d-4431216d3b1f

Approved on: 2021-06-07

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.343C>T

NM_000527.5(LDLR):c.343C>T (p.Arg115Cys)

ENST00000558518.6:c.343C>T

ENST00000252444.9:n.597C>T

ENST00000455727.6:c.314-2143C>T

ENST00000535915.5:c.220C>T

ENST00000545707.5:c.314-1316C>T

ENST00000557933.5:c.343C>T

ENST00000558013.5:c.343C>T

ENST00000558518.5:c.343C>T

NM_000527.4:c.343C>T

NM_001195798.1:c.343C>T

NM_001195799.1:c.220C>T

NM_001195800.1:c.314-2143C>T

NM_001195803.1:c.314-1316C>T

NM_001195798.2:c.343C>T

NM_001195799.2:c.220C>T

NM_001195800.2:c.314-2143C>T

NM_001195803.2:c.314-1316C>T

NC_000019.10:g.11105249C>T

CM000681.2:g.11105249C>T

NC_000019.9:g.11215925C>T

CM000681.1:g.11215925C>T

NC_000019.8:g.11076925C>T

NG_009060.1:g.20869C>T

Likely Pathogenic

PP4 PP3 PM2 PM1

BA1 BS2 BS4 BS3 BS1 PVS1 BP7 BP5 BP2 BP3 BP4 BP1 PS2 PS4 PS1 PS3 PP1 PP2 PM6 PM3 PM4 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.343C>T (p.Arg115Cys) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM1, PM2, 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: PM1 - Missense at codon 115. Variant meets PM2 and is in exon 4. PM2 - FAF = 0.0001446 (0.014%) in Latino/Admixed American exomes (gnomAD v2.1.1). PP3 - REVEL = 0.81. PP4 - Variant meets PM2. Identified in at least 1 FH case with clinical diagnosis of definite heterozygous hypercholesterolemia by DLCN score from PMID 16250003.

PP4

Variant meets PM2. Identified in at least 1 FH case with clinical diagnosis of definite heterozygous hypercholesterolemia by DLCN score from PMID 16250003. --- PP4 is Met

PP3

REVEL = 0.81. It is above 0.75, so PP3 is Met

PM2

FAF = 0.0001446 (0.014%) in Latino/Admixed American exomes (gnomAD v2.1.1). FAF is under 0.02%, so PM2 is Met

PM1

Missense at codon 115. Variant meets PM2 and is in exon 4, so PM1 is Met

BA1

FAF = 0.00005597 (0.006%) in Latino/Admixed American exomes (gnomAD v2.1.1). FAF is not above 0.5%, so BA1 is Not Met.

BS2

no unaffected individuals identified with the variant, so BS2 is Not Met

BS4

family members tested are compound heterozygotes for another variant. BS4 is Not Met

BS3

no functional assays performed, not applicable

BS1

FAF = 0.00005597 (0.006%) in Latino/Admixed American exomes (gnomAD v2.1.1). FAF is not above 0.2%, so BS1 is Not Met.

PVS1

Missense variant, PVS1 Not Met

BP7

Missense variant, so BP7 is not applicable

BP5

Not applicable

BP2

Variant identified in an index case with heterozygous FH phenotype and NM_000527.5(LDLR):c.977C>G p.Ser326Cys (ClinVar ID 251581), classified as Likely pathogenic by these guidelines, in trans, from Laboratory of Genetics and Molecular Cardiology. so BP2 is not met

BP3

Not applicable

BP4

REVEL = 0.81. It is not below 0.15 and PP3 is Met, so BP4 is Not Met

BP1

Not applicable

PS2

no de novo cases were identified, so PS2 is Not Met

PS4

Variant meets PM2. Identified in 1 index case with DLCN criteria for FH from PMID 16250003. Not enough evidence to meet PS4. --- PS4 is Not Met

PS1

Variant meets PM1, so PS1 is not applicable

PS3

no functional assays performed, not applicable

PP1

family members tested are compound heterozygotes for another variant. PP1 is Not Met

PP2

Not applicable

PM6

no de novo cases were identified, so PM6 is Not Met

PM3

not identified in individuals with other variants and homozygous FH phenotype --- PM3 is Not Met

PM4

Missense variant, not applicable

PM5

Variant meets PM1, so PM5 is not applicable

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