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.265T>C (p.Cys89Arg)

CA10584817

251102 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7f250f74-e4cd-4624-ad04-72229035c1dc

HGVS expressions

NM_000527.5:c.265T>C

NM_000527.5(LDLR):c.265T>C (p.Cys89Arg)

NC_000019.10:g.11102738T>C

CM000681.2:g.11102738T>C

NC_000019.9:g.11213414T>C

CM000681.1:g.11213414T>C

NC_000019.8:g.11074414T>C

NG_009060.1:g.18358T>C

ENST00000558518.6:c.265T>C

ENST00000252444.9:n.519T>C

ENST00000455727.6:c.265T>C

ENST00000535915.5:c.190+2393T>C

ENST00000545707.5:c.265T>C

ENST00000557933.5:c.265T>C

ENST00000557958.1:n.351T>C

ENST00000558013.5:c.265T>C

ENST00000558518.5:c.265T>C

NM_000527.4:c.265T>C

NM_001195798.1:c.265T>C

NM_001195799.1:c.190+2393T>C

NM_001195800.1:c.265T>C

NM_001195803.1:c.265T>C

NM_001195798.2:c.265T>C

NM_001195799.2:c.190+2393T>C

NM_001195800.2:c.265T>C

NM_001195803.2:c.265T>C

Likely Pathogenic

PS4_Supporting PP4 PP1 PP3 PM3 PM1 PM2

PVS1 BA1 BP2 BP4 BP7 BS2 BS4 BS3 BS1 PS2 PS3 PS1 PM4 PM5 PM6

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 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.265T>C (p.Cys89Arg) variant is classified as Likely pathogenic for Familial Hypercholesterolemia by applying evidence codes PM1, PM2, PM3, PS4_Supporting, PP1, PP3 and 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: PM1 - Variant meets PM2 and alters Cys89, one of the cysteine residues listed, so PM1 is Met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 18.05 mmol/L) and LDLR variant c.1775G>A/p.(Gly592Glu), classified as Pathogenic by these guidelines, in trans, from ltaly (PMID: 9974426), so PM3 is Met. PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases: 1 index case with possible FH (Simon-Broome criteria) from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, at least 1 index case with definite heterozygous FH from The Netherlands (PMID: 16250003), 1 index case fulfilling MedPed criteria for FH from Spain (PMID: 16627557), 2 index cases fulfilling WHO criteria for FH from Poland (PMID: 20145306), so PS4_Supporting is Met. PP1 - Variant segregates with FH phenotype in 3 informative meiosis from 1 family from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 2 affected family members have the variant and 1 non-affected family member does not have the variant, so PP1 is Met. PP3 - REVEL = 0.973. It is above 0.75, so PP3 is Met. PP4 - Variant meets PM2 and is identified in 5 unrelated index cases fulfilling clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met.

PS4_Supporting

Variant meets PM2 and is identified in 5 unrelated index cases: 1 index case with possible FH (Simon-Broome criteria) from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, at least 1 index case with definite heterozygous FH from The Netherlands (PMID: 16250003), 1 index case fulfilling MedPed criteria for FH from Spain (PMID: 16627557), 2 index cases fulfilling WHO criteria for FH from Poland (PMID: 20145306), so PS4_Supporting is Met.

PP4

PP1

Variant segregates with FH phenotype in 3 informative meiosis from 1 family from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 2 affected family members have the variant and 1 non-affected family member does not have the variant, so PP1 is Met.

PP3

REVEL = 0.973. It is above 0.75, so PP3 is Met.

PM3

Variant meets PM2 and is identified in an index case with homozygous FH phenotype (LDL = 18.05 mmol/L) and LDLR variant c.1775G>A/p.(Gly592Glu), classified as Pathogenic by these guidelines, in trans, from ltaly (PMID: 9974426), so PM3 is Met.

PM1

Variant meets PM2 and alters Cys89, one of the cysteine residues listed, so PM1 is Met.

PM2

This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.

PVS1

Variant is missense, so PVS1 is Not Met.

BA1

No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BA1 is Not Met.

BP2

BP4

REVEL = 0.973. It is not below 0.50, so BP4 is Not Met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BS2

Not observed in 208 non-FH alleles tested from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge, so BS2 is not met.

BS4

Lack of segregation data not reported, so BS4 is not met.

BS3

Functional studies are performed in compound heterozygous patients cells, so BS3 is not applicable.

BS1

No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BS1 is Not Met.

PS2

de novo occurrence data not reported, so PS2 is Not Met.

PS3

Functional studies are performed in compound heterozygous patients cells, so PS3 is not applicable.

PS1

Variant meets PM1 (alters Cys89, one of the cysteine residues listed), so PS1 is not met.

PM4

Variant meets PM2 and is missense, so PM4 is Not Met.

PM5

Variant meets PM1 (alters Cys89, one of the cysteine residues listed), so PM5 is not met.

PM6

de novo occurrence data not reported, so PM6 is Not Met.

Approved on: 2022-03-25

Published on: 2022-07-12

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.