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]

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Variant: NM_000527.5(LDLR):c.1966C>A (p.His656Asn)

CA037604

252136 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 29ba2878-e776-400d-a89d-3ebaa40d7543

HGVS expressions

NM_000527.5:c.1966C>A

NM_000527.5(LDLR):c.1966C>A (p.His656Asn)

ENST00000558518.6:c.1966C>A

ENST00000252444.9:n.2220C>A

ENST00000455727.6:c.1462C>A

ENST00000535915.5:c.1843C>A

ENST00000545707.5:c.1585C>A

ENST00000557933.5:c.1966C>A

ENST00000558013.5:c.1966C>A

ENST00000558518.5:c.1966C>A

ENST00000559340.1:n.547C>A

NM_000527.4:c.1966C>A

NM_001195798.1:c.1966C>A

NM_001195799.1:c.1843C>A

NM_001195800.1:c.1462C>A

NM_001195803.1:c.1585C>A

NM_001195798.2:c.1966C>A

NM_001195799.2:c.1843C>A

NM_001195800.2:c.1462C>A

NM_001195803.2:c.1585C>A

NC_000019.10:g.11120212C>A

CM000681.2:g.11120212C>A

NC_000019.9:g.11230888C>A

CM000681.1:g.11230888C>A

NC_000019.8:g.11091888C>A

NG_009060.1:g.35832C>A

Uncertain Significance

PP1_Strong PP4 PP3 PM2 BS3

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

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.1966C>A (p.His656Asn) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (BS3, PP1_Strong, 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: BS3 - PMID: 32015373 - Level 1 assay - study on heterologous cells (CHO-ldlA7), Western blot and FACS assays - results - Normal (95%) cell surface LDLR, LDL-LDLR binding (100%) and uptake (90-95%). ---- functional study is consistent with no damaging effect. PP1_strong - 1 family with 6 informative meiosis is reported by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. PM2 - PopMax MAF = 0.00002638 (0.0026%) in European non-Finnish exomes (gnomAD v2.1.1). PP3 - REVEL: 0,905. PP4 - Variant meets PM2. Variant is reported in 1 index case fulfills Simon-Broome criteria.

PP1_Strong

1 family with 6 informative meiosis (1 affected 1st degree family member, 1 affected sibling and 2 affected 2nd degree family members have the variant, plus 1 unaffected 1st degree family member and 1 unaffected sibling do not have the variant) is reported by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.

PP4

Variant meets PM2. Variant is reported in 1 index case fulfills Simon-Broome criteria (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge).

PP3

REVEL: 0,905. Score is above 0,75.

PM2

PopMax MAF = 0.00002638 (0.0026%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is below 0.02%.

BS3

PMID: 32015373 - Level 1 assay - study on heterologous cells (CHO-ldlA7), Western blot and FACS assays - results - Normal (95%) cell surface LDLR, LDL-LDLR binding (100%) and uptake (90-95%). ---- functional study is consistent with no damaging effect.

PS2

No de novo cases were identified.

PS4

Variant meets PM2. Variant identified only in 1 index case who fulfills Simon-Broome criteria (Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge). At least 2 cases are needed - PS4 is not met.

PS3

PMID: 32015373 - Level 1 assay - study on heterologous cells (CHO-ldlA7), Western blot and FACS assays - results - Normal (95%) cell surface LDLR, LDL-LDLR binding (100%) and uptake (90-95%). Variant results are not below 70% of WT activity in either experssion/biosythesis, binding or internalization. PS3 is not met.

PS1

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

BP2

Not identified in individuals with other variants.

BP3

Not applicable.

BP4

REVEL: 0,905. Score is not below 0,50.

BP1

Not applicable.

BP5

Not applicable.

BP7

Missense variant. Not applicable.

BA1

FAF = 0.000007010 (0.0007010%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.5%

PP2

Not applicable.

PM3

Not identified in individuals with other variants.

PM1

Missense at codon 656. 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

No other missense variants classified as Pathogenic by these guidelines. One missense variant described in the same codon (accessed 19 August 2020): (1)NM_000527.5(LDLR):c.1968C>G (p.His656Gln) (ClinVar ID 251903) - VUS by these guidelines.

PM6

No de novo cases were identified.

PVS1

Missense variant. Not applicable.

BS2

No unaffected individuals identified with the variant.

BS4

Only one family with non-segregations reported - at least two families are needed.

BS1

FAF = 0.000007010 (0.0007010%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.2%

Approved on: 2021-06-18

Published on: 2021-06-24

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