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_000527.4(LDLR):c.185C>G (p.Thr62Arg)

CA16602292

375775 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: f6dd9146-59ca-44c4-ac27-d16f23cce231

HGVS expressions

NM_000527.4:c.185C>G

NM_000527.4(LDLR):c.185C>G (p.Thr62Arg)

ENST00000558518.6:c.185C>G

ENST00000252444.9:n.439C>G

ENST00000455727.6:c.185C>G

ENST00000535915.5:c.185C>G

ENST00000545707.5:c.185C>G

ENST00000557933.5:c.185C>G

ENST00000557958.1:n.271C>G

ENST00000558013.5:c.185C>G

ENST00000558518.5:c.185C>G

ENST00000560502.5:n.271C>G

NM_001195798.1:c.185C>G

NM_001195799.1:c.185C>G

NM_001195800.1:c.185C>G

NM_001195803.1:c.185C>G

NM_000527.5:c.185C>G

NM_001195798.2:c.185C>G

NM_001195799.2:c.185C>G

NM_001195800.2:c.185C>G

NM_001195803.2:c.185C>G

NC_000019.10:g.11100340C>G

CM000681.2:g.11100340C>G

NC_000019.9:g.11211016C>G

CM000681.1:g.11211016C>G

NC_000019.8:g.11072016C>G

NG_009060.1:g.15960C>G

Uncertain Significance

PM2

PVS1 BS2 BS3 BS4 BS1 BP5 BP7 BP4 BP1 BP2 BP3 PS2 PS1 PS3 PS4 BA1 PP4 PP3 PP2 PP1 PM6 PM3 PM4 PM1 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_000527.4(LDLR):c.185C>G (p.Thr62Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2) 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: PM2 - No population data was found for this variant in gnomAD (gnomAD v2.1.1).

PM2

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

PVS1

Missense variant, PVS1 Not Met

BS2

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

BS3

no functional assays performed, not applicable

BS4

no family members were tested, so BS4 is Not Met

BS1

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

BP5

Not applicable

BP7

Missense variant, so BP7 is not applicable

BP4

REVEL = 0.612. It is not below 0.50, so BP4 is Not Met

BP1

Not applicable

BP2

not identified in individuals with other variants, so BP2 is Not Met

BP3

Not applicable

PS2

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

PS1

No variant described that leads to the same amino acid change, so PS1 is Not Met

PS3

no functional assays performed, not applicable

PS4

Variant meets PM2. But no information of FH cases with the variant was identified, so PS4 is Not Met

BA1

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

PP4

Variant meets PM2. But no information of FH cases with the variant was identified, so PP4 is Not Met

PP3

REVEL = 0.612. It is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) not on limits B) does not create GT C) there is a GT nearby: MES scores: variant cryptic site = 2.64, wt cryptic site = -5.58, canonical donor site = 7.39 Ratio variant cryptic/wild-type cryptic score = 2.64/-5.58 = -0.47 --- it is not above 1.1 Ratio variant cryptic donor/authentic donor score = 2.64/7.39 = 0.36 --- it is not above 0.9 ---- PP3 is not met

PP2

Not applicable

PP1

no family members were tested, so PP1 is Not Met

PM6

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

PM3

not identified in individuals with other variants, so PM3 is Not Met

PM4

Missense variant, not applicable

PM1

Missense at codon 62. PM2 is Met, but it is not exon 4 or any of the 60 Cys residues listed, so PM1 is Not Met

PM5

One more missense variant described in same codon: (1)NM_000527.5(LDLR):c.185C>T (p.Thr62Met) (ClinVar ID 161273) - VUS by these guidelines --- VUS, so PM5 is Not Met

Approved on: 2021-06-23

Published on: 2021-06-24

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