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.1965C>G (p.Phe655Leu)

CA10585700

252135 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: f4f2a927-e1d2-47a5-a59b-828b25fd786a

HGVS expressions

NM_000527.5:c.1965C>G

NM_000527.5(LDLR):c.1965C>G (p.Phe655Leu)

ENST00000558518.6:c.1965C>G

ENST00000252444.9:n.2219C>G

ENST00000455727.6:c.1461C>G

ENST00000535915.5:c.1842C>G

ENST00000545707.5:c.1584C>G

ENST00000557933.5:c.1965C>G

ENST00000558013.5:c.1965C>G

ENST00000558518.5:c.1965C>G

ENST00000559340.1:n.546C>G

NM_000527.4:c.1965C>G

NM_001195798.1:c.1965C>G

NM_001195799.1:c.1842C>G

NM_001195800.1:c.1461C>G

NM_001195803.1:c.1584C>G

NM_001195798.2:c.1965C>G

NM_001195799.2:c.1842C>G

NM_001195800.2:c.1461C>G

NM_001195803.2:c.1584C>G

NC_000019.10:g.11120211C>G

CM000681.2:g.11120211C>G

NC_000019.9:g.11230887C>G

CM000681.1:g.11230887C>G

NC_000019.8:g.11091887C>G

NG_009060.1:g.35831C>G

Likely Pathogenic

PM2 PP1_Strong PS4_Supporting PP4

PS2 PS3 PS1 PM6 PM3 PM1 PM4 PM5 BA1 PVS1 BP5 BP7 BP2 BP3 BP4 BP1 BS4 BS3 BS1 BS2 PP3 PP2

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.1965C>G (p.Phe655Leu) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PP1_Strong, PM2, PP4 and PS4_Supportive) 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_strong - Segregation data are published in PMID: 8634338 = 6 informative meiosis. PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1). PP4 - Variant meets PM2. 2 cases fulfilling Simon-Broome criteria published in PMID: 8634338. PS4_supporting - Variant meets PM2. Variant identified in 2 unrelated index cases (2 cases fulfilling Simon-Broome criteria published in PMID: 8634338).

PM2

No population data was found for this variant in gnomAD (gnomAD v2.1.1)

PP1_Strong

Segregation data are published in PMID: 8634338 (family of index case #1: 2 affected 1st degree family members (LDL-C 7.1mmol/L, 5.3mmol/L) have the variant and 2 unaffected 1st degree family members (LDL-C 2.8mmol/L, 2.9mmol/L) do not have the variant. family of case index #2: 1 affected 1st degree family member (LDL-C 6.5mmol/L) has the variant and 1 unaffected 1st degree family member (LDL-C 3.4mmol/L) does not have the variant) = 6 informative meiosis.

PS4_Supporting

Variant meets PM2. Variant identified in 2 unrelated index cases (2 cases fulfilling Simon-Broome criteria published in PMID: 8634338).

PP4

Variant meets PM2. 2 cases fulfilling Simon-Broome criteria published in PMID: 8634338

PS2

No de novo cases were identified.

PS3

No functional assays performed/found - not applicable.

PS1

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

PM6

No de novo cases were identified.

PM3

Not identified in individuals with other variants.

PM1

Missense at codon 655. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed. Not applicable.

PM4

Missense variant. Not applicable.

PM5

This variant is the only variant found in this codon in ClinVar (assessed 4 June 2020).

BA1

No population data was found for this variant in gnomAD (gnomAD v2.1.1)

PVS1

Missense variant. Not applicable.

BP5

Not applicable.

BP7

Missense variant. Not applicable.

BP2

Not identified in individuals with other variants.

BP3

Not applicable.

BP4

REVEL: 0,661. Score is not below 0,50.

BP1

Not applicable.

BS4

No non-segregations were identified/found.

BS3

No functional assays performed/found - not applicable.

BS1

No population data was found for this variant in gnomAD (gnomAD v2.1.1)

BS2

No unaffected individuals identified with the variant.

PP3

REVEL: 0,661. Score is not above 0,75. Splicing predictors - negative.

PP2

Not applicable.

Approved on: 2021-06-18

Published on: 2021-06-24

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.