Variant: NM_000527.5(LDLR):c.269A>G (p.Asp90Gly)

CA042622

226313 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: 243fe145-86fd-48f6-98dd-c946485388c0

Approved on: 2021-12-30

Published on: 2022-07-11

HGVS expressions

NM_000527.5:c.269A>G
NM_000527.5(LDLR):c.269A>G (p.Asp90Gly)
NC_000019.10:g.11102742A>G
CM000681.2:g.11102742A>G
NC_000019.9:g.11213418A>G
CM000681.1:g.11213418A>G
NC_000019.8:g.11074418A>G
NG_009060.1:g.18362A>G
ENST00000558518.6:c.269A>G
ENST00000252444.9:n.523A>G
ENST00000455727.6:c.269A>G
ENST00000535915.5:c.190+2397A>G
ENST00000545707.5:c.269A>G
ENST00000557933.5:c.269A>G
ENST00000557958.1:n.355A>G
ENST00000558013.5:c.269A>G
ENST00000558518.5:c.269A>G
NM_000527.4:c.269A>G
NM_001195798.1:c.269A>G
NM_001195799.1:c.190+2397A>G
NM_001195800.1:c.269A>G
NM_001195803.1:c.269A>G
NM_001195798.2:c.269A>G
NM_001195799.2:c.190+2397A>G
NM_001195800.2:c.269A>G
NM_001195803.2:c.269A>G

Pathogenic

• Met criteria codes: PP1_Moderate PM3 PM5 PM2 PS4 PP4 PP3

• Not Met criteria codes: BA1 PM1 PM4 PM6 BS2 BS4 BS3 BS1 BP2 BP3 BP4 BP1 BP5 BP7 PVS1 PS2 PS3 PS1 PP2

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.269A>G (p.Asp90Gly) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS4, PP1_Moderate, PM2, PM3, PM5, 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: PS4 - variant meets PM2 and was identified in at least 14 unrelated index cases with clinical criteria of FH: - 4 unrelated index cases with DLCN >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia; - at least 1 index case with DLCN probable FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583646.1), France; - 8 unrelated index cases (7 with DLCN>=6 and 1 SB possible) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France; - at least 1 index case with SB criteria for FH (plasma cholesterol of >8.0 mmol/L and family histories of hypercholesterolemia and/or classical clinical stigmata of FH) from PMID 11857755 (Bunn et al., 2002), New Zeland; - 1 index case with SB criteria for FH (grossly increased plasma cholesterol concentration and the presence of xanthomata in childhood and cardiovascular involvement by puberty in the proband, together with hypercholesterolemia in both parents; this index case died at 31years, had cholesterol of 20.7mmol/L and CVD) from PMID 9026534 (Webb et al., 1996), UK so PS4 is met. PP1_moderate - Variant segregates with FH phenotype in 5 informative meiosis from 3 families: - 2 affected family members have the variant, from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA); - 3 affected family members have the variant, from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), so PP1_Moderate is met. PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met. PM3 - variant meets PM2 and was identified in - 1 index case with phenotype of homozygous FH (cholesterol of 20.7mmol/L) and also NM_000527.5(LDLR):c.912C>G (p.Asp304Glu), Likely pathogenic by these guidelines, from PMID 9026534 (Webb et al., 1996), UK so PM3 is met PM5 - 4 other missense variants is the same codon: - NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines - NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelines There is 1 variant classified as Pathogenic by these guidelines, so PM5 is met. PP3 - REVEL = 0.957. It is above 0.75, so PP3 is met PP4 - variant meets PM2 and was identified in at least 14 unrelated index cases with clinical criteria of FH (see PS4 for details), so PP4 is met

Met criteria codes

• PP1_Moderate: Variant segregates with FH phenotype in 5 informative meiosis from 3 families: - 2 affected family members have the variant, from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA) - 3 affected family members have the variant, from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière) so PP1_Moderate is met
• PM3: variant meets PM2 and was identified in - 1 index case with phenotype of homozygous FH (cholesterol of 20.7mmol/L) and also NM_000527.5(LDLR):c.912C>G (p.Asp304Glu), Likely pathogenic by these guidelines, from PMID 9026534 (Webb et al., 1996), UK so PM3 is met
• PM5: 4 other missense variants is the same codon: - NM_000527.5(LDLR):c.268G>A (p.Asp90Asn) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.268G>T (p.Asp90Tyr) - classified as Likely pathogenic​ by the FH VCEP, with these guidelines - NM_000527.5(LDLR):c.269A>C (p.Asp90Ala) - Likely pathogenic by these guidelines - NM_000527.5(LDLR):c.270T>A (p.Asp90Glu) - Pathogenic by these guidelines There is 1 variant classified as Pathogenic by these guidelines, so PM5 is met.
• PM2: This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is met.
• PS4: variant meets PM2 and was identified in at least 14 unrelated index cases with clinical criteria of FH: - 4 unrelated index cases with DLCN >=6 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Australia; - at least 1 index case with DLCN probable FH from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583646.1), France; - 8 unrelated index cases (7 with DLCN>=6 and 1 SB possible) from Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies (APHP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière), France - at least 1 index case with SB criteria for FH (plasma cholesterol of >8.0 mmol/L and family histories of hypercholesterolemia and/or classical clinical stigmata of FH) from PMID 11857755 (Bunn et al., 2002), New Zeland; - 1 index case with SB criteria for FH (grossly increased plasma cholesterol concentration and the presence of xanthomata in childhood and cardiovascular involvement by puberty in the proband, together with hypercholesterolemia in both parents; this index case died at 31years, had cholesterol of 20.7mmol/L and CVD) from PMID 9026534 (Webb et al., 1996), UK so PS4 is met
• PP4: variant meets PM2 and was identified in at least 14 unrelated index cases with clinical criteria of FH (see PS4 for details) so PP4 is met
• PP3: REVEL = 0.957. It is above 0.75, so PP3 is met

Not Met criteria codes

• BA1: This variant is absent from gnomAD (gnomAD v2.1.1), so not met
• PM1: variant is not in exon 4 and does not alter Cys, so not met
• PM4: variant is missense, so not met
• PM6: no de novo occurrence
• BS2: not identified in normolipidemic individuals, so not met
• BS4: no lack of segregation was identified, so not met
• BS3: only functional study on compound heterozygous individual, so not met
• BS1: This variant is absent from gnomAD (gnomAD v2.1.1), so not met
• BP2: no index case with more than 1 variant and heterozygous phenotype was identified, so not met
• BP3: not applicable
• BP4: REVEL = 0.957. It is not below 0.50, so BP4 is not met
• BP1: not applicable
• BP5: not applicable
• BP7: variant is missense, so not met
• PVS1: variant is missense and not in initiation codon, so not met
• PS2: no de novo occurrence
• PS3: only functional study on compound heterozygous individual, so not met
• PS1: no other missense variant leads to the same amino acid change in the same codon, so not met
• PP2: not applicable