Evidence Repository
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.1816G>T (p.Ala606Ser)

CA023592

161264 (ClinVar)

Gene: LDLR
Condition: hypercholesterolemia, familial
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 53a6114d-d0ac-4c36-b589-da6298a96154
Approved on: 2021-06-09
Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.1816G>T
NM_000527.5(LDLR):c.1816G>T (p.Ala606Ser)
ENST00000558518.6:c.1816G>T
ENST00000252444.9:n.2070G>T
ENST00000455727.6:c.1312G>T
ENST00000535915.5:c.1693G>T
ENST00000545707.5:c.1435G>T
ENST00000557933.5:c.1816G>T
ENST00000558013.5:c.1816G>T
ENST00000558518.5:c.1816G>T
ENST00000559340.1:n.426+757G>T
NM_000527.4:c.1816G>T
NM_001195798.1:c.1816G>T
NM_001195799.1:c.1693G>T
NM_001195800.1:c.1312G>T
NM_001195803.1:c.1435G>T
NM_001195798.2:c.1816G>T
NM_001195799.2:c.1693G>T
NM_001195800.2:c.1312G>T
NM_001195803.2:c.1435G>T
NC_000019.10:g.11116969G>T
CM000681.2:g.11116969G>T
NC_000019.9:g.11227645G>T
CM000681.1:g.11227645G>T
NC_000019.8:g.11088645G>T
NG_009060.1:g.32589G>T

Uncertain Significance

Met criteria codes 1
PP1
Not Met criteria codes 25
BA1 PS2 PS4 PS3 PS1 PP4 PP3 PP2 PM3 PM1 PM4 PM5 PM6 PM2 BS2 BS4 BS3 BS1 BP5 BP7 BP2 BP3 BP4 BP1 PVS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Familial Hypercholesterolemia VCEP
The NM_000527.5(LDLR):c.1816G>T (p.Ala606Ser) variant is classified as variant of Uncertain significance for Familial Hypercholesterolemia by applying evidence codes (PP1) 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 - 2 informative meioses identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.
Met criteria codes
PP1
2 informative meioses identified by Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge.
Not Met criteria codes
BA1
FAF = 0.0001156 (0.01156%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.5%.
PS2
No de novo cases were identified.
PS4
Variant does not meet PM2.
PS3
No in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
PS1
No variant described that leads to the same amino acid change.
PP4
Variant does not meet PM2.
PP3
REVEL: 0,6. Score is not above 0,75. Splicing predictors - negative.
PP2
Not applicable.
PM3
Variant does not meet PM2, not applicable
PM1
Missense at codon 606. PM2 is not Met, 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 in the same codon. Two other missense variants described in the same codon (accessed 19 August 2020): (1)NM_000527.5(LDLR):c.1816G>A (p.Ala606Thr) (ClinVar ID 252046) - classified as VUS by these guidelines. (2)NM_000527.4(LDLR):c.1817C>A (p.Ala606Asp) (ClinVar ID 440663) - classified as VUS by these guidelines.
PM6
No de novo cases were identified.
PM2
PopMax MAF = 0.0002323 (0.023%) in European non-Finnish exomes (gnomAD v2.1.1). MAF is not below 0.02%.
BS2
No unaffected individuals identified with the variant.
BS4
1 affected sibling without the variant from Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge. 2 cases in 2 families are needed for BS4. BS4 is not met.
BS3
No in vitro or in vivo functional studies showing non-damaging effect on protein function or splicing.
BS1
FAF = 0.0001156 (0.01156%) in European non-Finnish exomes (gnomAD v2.1.1). FAF is not above 0.2%.
BP5
Not applicable.
BP7
Missense variant. Not applicable.
BP2
Insuficient information about cases.
BP3
Not applicable.
BP4
REVEL: 0,6. Score is not below 0,15.
BP1
Not applicable.
PVS1
Missense variant. Not applicable.
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