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]

Variant: NM_000527.5(LDLR):c.1171G>A (p.Ala391Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA023426

183138 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7235c54a-6e6c-4107-b0ea-465ee2900bc7

Approved on: 2021-06-23

Published on: 2021-06-24

HGVS expressions

NM_000527.5:c.1171G>A

NM_000527.5(LDLR):c.1171G>A (p.Ala391Thr)

ENST00000558518.6:c.1171G>A

ENST00000252444.9:n.1425G>A

ENST00000455727.6:c.667G>A

ENST00000535915.5:c.1048G>A

ENST00000545707.5:c.790G>A

ENST00000557933.5:c.1171G>A

ENST00000558013.5:c.1171G>A

ENST00000558518.5:c.1171G>A

ENST00000560173.1:n.170G>A

ENST00000560467.1:n.651G>A

NM_000527.4:c.1171G>A

NM_001195798.1:c.1171G>A

NM_001195799.1:c.1048G>A

NM_001195800.1:c.667G>A

NM_001195803.1:c.790G>A

NM_001195798.2:c.1171G>A

NM_001195799.2:c.1048G>A

NM_001195800.2:c.667G>A

NM_001195803.2:c.790G>A

NC_000019.10:g.11111624G>A

CM000681.2:g.11111624G>A

NC_000019.9:g.11222300G>A

CM000681.1:g.11222300G>A

NC_000019.8:g.11083300G>A

NG_009060.1:g.27244G>A

Benign

BA1 BS2 BP2 BP4

PVS1 PS1 PS2 PS4 PS3 PP4 PP1 PP3 PP2 PM6 PM2 PM5 PM3 PM1 PM4 BS4 BS3 BS1 BP5 BP7 BP3 BP1

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_000527.5(LDLR):c.1171G>A (p.Ala391Thr) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BA1, BS2, BP2 and BP4 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: BA1 - FAF = 0.1752 (17.52%) in African exomes (gnomAD v2.1.1); frequency meets BA1 >0.5% BS2 - Case-level data in VCI indicates this variant is identified in heterozygosity in 1894 normolipidemic individuals, as well as in homozygosity in 58 normolipidemic individuals. BP2 - Case-level data present in VCI indicates this variant has been identified to co-occur with Pathogenic LDLR variants in at least 3 index cases with heterozygous FH phenotype. BP4 - REVEL = 0.309; score is below BP4 threshold of <0.50. splicing evaluation is required. Functional data on splicing not available. A) not on limits B) does not create GT C) no nearby GT.

BA1

FAF = 0.1752 (17.52%) in African exomes (gnomAD v2.1.1); frequency meets BA1 >0.5%

BS2

Case-level data in VCI indicates this variant is identified in heterozygosity in 1894 normolipidemic individuals (1891 from Color and 3 from Western University), as well as in homozygosity in 58 normolipidemic individuals (all from Color).

BP2

Case-level data present in VCI indicates this variant has been identified to co-occur with Pathogenic LDLR variants in at least 3 index cases with heterozygous FH phenotype: - 1 index case from INSA with heterozygous FH phenotype is also heterozygous for LDLR c.631C>G/p.(His211Asp), Pathogenic by these guidelines; - 1 index case from INSA with heterozygous FH phenotype is also heterozygous for LDLR c.-57_67+56del (EX1del), Pathogenic by these guidelines; - 1 index case from Color with heterozygous FH phenotype is also heterozygous for LDLR:c.530C>T(p.Ser177Leu), Pathogenic by these guidelines;

BP4

REVEL = 0.309; score is below BP4 threshold of <0.50. splicing evaluation is required. Functional data on splicing not available. A) not on limits B) does not create GT C) no nearby GT BP4 is met.

PVS1

NA; missense variant

PS1

no other variants in same codon

PS2

No de novo data

PS4

PM2 caveat not met

PS3

No functional studies in literature

PP4

PM2 caveat is not met

PP1

No segregation data available

PP3

REVEL = 0.309; score is not above PP3 threshold of >0.75. splicing evaluation is required. Functional data on splicing not available. A) not on limits B) does not create GT C) no nearby GT PP3 is not met

PP2

PM6

No de novo data

PM2

PopMax MAF = 0.1814 (18.14%) in African exomes (gnomAD v2.1.1)

PM5

no other variants in same codon

PM3

PM2 caveat is not met

PM1

NA; not in exon 4 or at a CYS (PM2 caveat not met anyway)

PM4

NA; missense variant

BS4

No segregation data available

BS3

No functional studies in literature

BS1

BA1 is met

BP5

BP7

NA; missense variant

BP3

BP1

Curation History

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