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.932A>C (p.Lys311Thr)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA10585200

251531 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 4792b635-e961-4626-a094-25b7b23babb6

Approved on: 2022-01-14

Published on: 2022-07-12

HGVS expressions

NM_000527.5:c.932A>C

NM_000527.5(LDLR):c.932A>C (p.Lys311Thr)

NC_000019.10:g.11107506A>C

CM000681.2:g.11107506A>C

NC_000019.9:g.11218182A>C

CM000681.1:g.11218182A>C

NC_000019.8:g.11079182A>C

NG_009060.1:g.23126A>C

ENST00000558518.6:c.932A>C

ENST00000252444.9:n.1186A>C

ENST00000455727.6:c.428A>C

ENST00000535915.5:c.809A>C

ENST00000545707.5:c.551A>C

ENST00000557933.5:c.932A>C

ENST00000558013.5:c.932A>C

ENST00000558518.5:c.932A>C

ENST00000558528.1:n.447A>C

ENST00000560467.1:n.532A>C

NM_000527.4:c.932A>C

NM_001195798.1:c.932A>C

NM_001195799.1:c.809A>C

NM_001195800.1:c.428A>C

NM_001195803.1:c.551A>C

NM_001195798.2:c.932A>C

NM_001195799.2:c.809A>C

NM_001195800.2:c.428A>C

NM_001195803.2:c.551A>C

Uncertain Significance

PP3 PM2

PS2 PS4 PS3 PS1 PP4 PP1 PM3 PM1 PM4 PM5 PVS1 PM6 BA1 BS2 BS4 BS3 BS1 BP7 BP2 BP4

Evidence Links 0

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.932A>C (p.Lys311Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PM3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006488 (0.006488%) in European (non-Finnish) genomes (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.787. It is above 0.75, so PP3 is Met.

PP3

REVEL = 0.787. It is above 0.75, so PP3 is Met.

PM2

PopMax MAF = 0.00006488 (0.006488%) in European (non-Finnish) genomes (gnomAD v2.1.1), so PM2 is Met.

PS2

de novo occurrence data not reported, so PS2 is Not Met.

PS4

Variant meets PM2, but case-control data not reported, so PS4 is Not Met.

PS3

There are no functional studies reported for this variant, so PS3 is not met.

PS1

No more missense variants that lead to the same amino acid change, so PS1 is Not Met.

PP4

Variant meets PM2 but phenotype data is not reported, so PP4 is Not Met.

PP1

Segregation data not reported, so PP1 is Not Met.

PM3

Observed in trans with other variant but phenotype not reported, so PM3 is Not Met.

PM1

Variant meets PM2 but is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.

PM4

Variant meets PM2 and is missense, so PM4 is Not Met.

PM5

One other missense variant in the same codon: - NM_000527.5(LDLR):c.932A>G (p.Lys311Arg) (ClinVar ID: 251532) - VUS by these guidelines There are no variants in the same codon classified as Pathogenic by these guidelines, so PM5 is not met.

PVS1

Variant is missense, so PVS1 is Not Met.

PM6

de novo occurrence data not reported, so PM6 is Not Met.

BA1

No FAF, just total MAF = 0.00003189 (0.003189%) in genomes (gnomAD v2.1.1), so BA1 is not met.

BS2

No control individuals tested, so BS2 is Not Met.

BS4

Lack of segregation data not reported, so BS4 is Not Met.

BS3

There are no functional studies reported for this variant, so BS3 is not met.

BS1

No FAF, just total MAF = 0.00003189 (0.003189%) in genomes (gnomAD v2.1.1), so BS1 is not met.

BP7

Variant is not synonymous, so BP7 is Not Met.

BP2

Observed in trans with other variant but phenotype not reported, so PM3 is Not Met.

BP4

REVEL = 0.787. It is not below 0.50, so BP4 is Not Met.

Curation History

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.