Variant: NM_000527.5(LDLR):c.932A>G (p.Lys311Arg)

CA10585201

251532 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 90aeb31d-3ff8-43b2-beb2-f6e2d74835d3

Approved on: 2022-01-17

Published on: 2022-07-12

HGVS expressions

NM_000527.5:c.932A>G
NM_000527.5(LDLR):c.932A>G (p.Lys311Arg)
NC_000019.10:g.11107506A>G
CM000681.2:g.11107506A>G
NC_000019.9:g.11218182A>G
CM000681.1:g.11218182A>G
NC_000019.8:g.11079182A>G
NG_009060.1:g.23126A>G
ENST00000558518.6:c.932A>G
ENST00000252444.9:n.1186A>G
ENST00000455727.6:c.428A>G
ENST00000535915.5:c.809A>G
ENST00000545707.5:c.551A>G
ENST00000557933.5:c.932A>G
ENST00000558013.5:c.932A>G
ENST00000558518.5:c.932A>G
ENST00000558528.1:n.447A>G
ENST00000560467.1:n.532A>G
NM_000527.4:c.932A>G
NM_001195798.1:c.932A>G
NM_001195799.1:c.809A>G
NM_001195800.1:c.428A>G
NM_001195803.1:c.551A>G
NM_001195798.2:c.932A>G
NM_001195799.2:c.809A>G
NM_001195800.2:c.428A>G
NM_001195803.2:c.551A>G

Uncertain Significance

• Met criteria codes: PM3 PM2 PP4

• Not Met criteria codes: PM1 PM4 PM5 PM6 BA1 BS2 BS4 BS3 BS1 BP2 BP4 PVS1 BP7 PS2 PS4 PS3 PS1 PP1 PP3

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

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.932A>G (p.Lys311Arg) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PM3 and PP4) 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 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PM3 - Variant meets PM2 and is identified in an index case with homozygous FH phenotype (plasma cholesterol > 600mg/dL) and LDLR variant NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID: 251517), classified as Likely pathogenic by these guidelines, in trans (PMID: 1301940), so PM3 is Met. PP4 - Variant meets PM2 and is identified in 1 index-case with SB/DLCN score of definite FH (plasma cholesterol > 600mg/dL with tendon xanthomas) from France (PMID: 1301940), so PP4 is Met.

Met criteria codes

• PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (plasma cholesterol > 600mg/dL) and LDLR variant NM_000527.5(LDLR):c.910G>T (p.Asp304Tyr) (ClinVar ID: 251517), classified as Likely pathogenic by these guidelines, in trans (PMID: 1301940), so PM3 is Met.
• PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met.
• PP4: Variant meets PM2 and is identified in 1 index-case with SB/DLCN score of definite FH (plasma cholesterol > 600mg/dL with tendon xanthomas) from France (PMID: 1301940), so PP4 is Met.

Not Met criteria codes

• 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>C (p.Lys311Thr) (ClinVar ID: 251531) - VUS by these guidelines There are no variants in the same codon classified as Pathogenic by these guidelines, so PM5 is not met.
• PM6: de novo occurrence data not reported, so PM6 is Not Met.
• BA1: No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BA1 is Not Met.
• BS2: No control individuals tested, so BS2 is Not Met.
• BS4: Lack of segregation not reported, so BS4 is Not Met.
• BS3: There are no functional studies reported for this variant, so BS3 is not met.
• BS1: No population data was found for this variant in gnomAD (gnomAD v2.1.1), so BA1 is Not Met.
• BP2: Identified in an index case with homozygous FH phenotype, so BP2 is not met.
• BP4: REVEL = 0.582. It is not below 0.50, so BP4 is Not Met.
• PVS1: Variant is missense, so PVS1 is Not Met.
• BP7: Variant is not synonymous, so BP7 is Not Met.
• PS2: de novo occurrence data not reported, so PS2 is Not Met.
• PS4: Variant meets PM2 and is identified in only 1 index-case with SB/DLCN score of definite FH (plasma cholesterol > 600mg/dL with tendon xanthomas) from France (PMID: 11810272), 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.
• PP1: Segregation data not reported, so PP1 is Not Met.
• PP3: REVEL = 0.582, it is not above 0.75, splicing evaluation required. Functional data on splicing not available. A) variant not on limits B) variant does not create GT C) no GT nearby ---PP3 is not met.