Variant: NM_000527.5(LDLR):c.1706-10G>A

CA035940

226368 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: def4fe9c-fe45-47b3-a4a1-f88eff12dde1

Approved on: 2022-03-16

Published on: 2022-04-19

HGVS expressions

NM_000527.5:c.1706-10G>A
NM_000527.5(LDLR):c.1706-10G>A
NC_000019.10:g.11116849G>A
CM000681.2:g.11116849G>A
NC_000019.9:g.11227525G>A
CM000681.1:g.11227525G>A
NC_000019.8:g.11088525G>A
NG_009060.1:g.32469G>A
ENST00000558518.6:c.1706-10G>A
ENST00000252444.9:n.1960-10G>A
ENST00000455727.6:c.1202-10G>A
ENST00000535915.5:c.1583-10G>A
ENST00000545707.5:c.1325-10G>A
ENST00000557933.5:c.1706-10G>A
ENST00000558013.5:c.1706-10G>A
ENST00000558518.5:c.1706-10G>A
ENST00000559340.1:n.426+637G>A
NM_000527.4:c.1706-10G>A
NM_001195798.1:c.1706-10G>A
NM_001195799.1:c.1583-10G>A
NM_001195800.1:c.1202-10G>A
NM_001195803.1:c.1325-10G>A
NM_001195798.2:c.1706-10G>A
NM_001195799.2:c.1583-10G>A
NM_001195800.2:c.1202-10G>A
NM_001195803.2:c.1325-10G>A

Likely Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: PP1_Moderate BS1 BS3_Supporting

• Not Met criteria codes: BA1 PM3 PM1 PM4 PM5 PM6 PM2 BS2 BS4 BP2 BP4 BP7 PVS1 PS4 PS2 PS1 PS3 PP4 PP3

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1706-10G>A variant is classified as Likely benign for Familial Hypercholesterolemia by applying evidence codes BS1, BS3_supporting and PP1_moderate 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: BS1 - FAF = 0.002911 (0.2911%) in Latino/Admixed American exomes (gnomAD v2.1.1), so BS1 is Met. BS3_supporting - 2 Level 3 assays: PMID: 25741862: Heterozygous patients' lymphocytes, RNA assays - result - Normal LDLR transcripts identified by sequencing. PMID: 19208450: Heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays - result - Normal LDLR transcripts, 43% of mutant transcripts (from total transcripts) in htz cells. ---- Aberrant transcripts are not detected, so BS3_Supporting is Met. PP1_moderate - Variant segregates with FH phenotype in at least 5 informative meiosis from 2 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 5 affected family members have the variant, so PP1_Moderate is Met. Variant has 1 Strong plus 1 Supporting evidence codes towards Benign, enough to classify as Likely benign and only 1 Moderate evidence code towards Pathogenic, not enough for Likely pathogenic, so we are confident in classifying this variant as Likely benign.

Met criteria codes

• PP1_Moderate: Variant segregates with FH phenotype in at least 5 informative meiosis from 2 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 5 affected family members have the variant, so PP1_Moderate is Met.
• BS1: FAF = 0.002911 (0.2911%) in Latino/Admixed American exomes (gnomAD v2.1.1), so BS1 is Met.
• BS3_Supporting: 2 Level 3 assays: PMID: 25741862: Heterozygous patients' lymphocytes, RNA assays - result - Normal LDLR transcripts identified by sequencing. PMID: 19208450: Heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays - result - Normal LDLR transcripts, 43% of mutant transcripts (from total transcripts) in htz cells. ---- Aberrant transcripts are not detected, so BS3_Supporting is Met.

Not Met criteria codes

• BA1: FAF = 0.002911 (0.2911%) in Latino/Admixed American exomes (gnomAD v2.1.1), so BA1 is not met.
• PM3: Variant does not meet PM2, so PM3 is Not Met.
• PM1: Variant does not meet PM2. Also is not located in exon 4 or alters a cysteine residues, so PM1 is Not Met.
• PM4: Variant does not meet PM2 and is not due to in-frame deletions/insertions, so PM4 is not met.
• PM5: Variant is in a non-coding region, so PM5 is Not Met.
• PM6: de novo occurrence data not reported, so PM6 is Not Met.
• PM2: PopMax MAF = 0.004147 (0.4147%) in Ashkenazi Jews exomes+genomes (gnomAD v2.1.1), so PM2 is not met.
• BS2: Variant identified in only 1 heterozygous individual in 120 non-FH individuals from rCardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, so BS2 is not met.
• BS4: Variant does not segregate with FH phenotype in 2 informative meiosis from 2 families from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge: 1 unaffected family member carries the variant and 1 affected family member does not carries the variant. Data does not include >= 2 informative meioses in each family, so BS4 is not met.
• BP2: Observed in trans with other variant but index case does not fulfill SB criteria, so BP2 is Not Met.
• BP4: No REVEL, splicing evaluation needed. Functional data on splicing, so BP4 is not applicable.
• BP7: Variant is not synonymous, so BP7 is Not Met.
• PVS1: Variant is not in canonical +/- 1,2 GT/AG splice site that predict a frameshift, so PVS1 is Not Met.
• PS4: Variant does not meet PM2, so PS4 is Not Met.
• PS2: de novo occurrence data not reported, so PS2 is Not Met.
• PS1: Variant is in a non-coding region, so PS1 is Not Met.
• PS3: 2 Level 3 assays: PMID: 25741862: Heterozygous patients' lymphocytes, RNA assays - result - Normal LDLR transcripts identified by sequencing. PMID: 19208450: Heterozygous patients' Epstein Barr virus transformed lymphocytes, RNA assays - result - Normal LDLR transcripts, 43% of mutant transcripts (from total transcripts) in htz cells. ---- Aberrant transcripts are not detected, so PS3 is not met.
• PP4: Variant does not meet PM2, so PP4 is Not Met.
• PP3: No REVEL, splicing evaluation needed. Functional data on splicing, so PP3 is not applicable.