Variant classification summary

NM_000527.5:c.691T>G

LDLR · NP_000518.1:p.(Cys231Gly) · NM_000527.5

GRCh37: chr19:11216273 T>G · GRCh38: chr19:11105597 T>G

Gene: LDLR Transcript: NM_000527.5

Final call

VUS

PM1 moderate PM2 moderate PP3 supporting

Variant details

Gene

LDLR

Transcript

NM_000527.5

Protein

NP_000518.1:p.(Cys231Gly)

gnomAD AF

1.9308274625451653e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 Moderate: the missense variant is in LDLR exon 4 and meets the PM2 frequency caveat.

2

PM2 Moderate: the highest observed gnomAD population frequency is below 0.0002.

3

PP3 Supporting: REVEL 0.85 exceeds the VCEP threshold of 0.75.

Final determination: Under ACMG/AMP 2015 Table 5, 2 Moderate plus 1 Supporting pathogenic criteria satisfy neither a pathogenic nor likely pathogenic rule, and no benign rule is satisfied, so the call is VUS.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: c.691T>G is a missense p.(Cys231Gly) substitution, not a qualifying loss-of-function consequence for the VCEP PVS1 pathway.	cspec pvs1_variant_assessment
PS1	Not met	Not met: no distinct pathogenic missense variant at codon 231 producing the same Cys-to-Gly change through a different nucleotide change was documented.	cspec PMID:10090473 PMID:10422804 PMID:11313767 spliceai
PS2	Not assessed	Not assessed: no confirmed de novo occurrence with documented maternity, paternity, and absent family history is reported for c.691T>G.	cspec PMID:11313767 PMID:16424354 PMID:19073363
PS3	Not assessed	Not assessed: a ClinVar submission reports 30–40% activity, but the primary assay, endpoint, required controls, and PMID 37719435 are unavailable for VCEP strength calibration.	cspec clinvar
PS4	Not assessed	Not assessed: exact-variant FH case count is not established, although PM2 is met with maximum gnomAD subpopulation AF 0.0000554262 <= 0.0002.	cspec gnomad_v2 gnomad_v4 PMID:10090473 PMID:10422804 PMID:11313767 PMID:16424354 PMID:19073363
PM1	Met	Met at Moderate: the missense variant is in LDLR exon 4 and its gnomAD v4.1 frequency is 1.93e-06, below the 0.0002 PM2 requirement.	cspec gnomad_v4
PM2	Met	Met at Moderate: the highest observed gnomAD population frequency is 5.741e-05 (0.00574%), below the VCEP PopMax MAF threshold of 0.0002 (0.02%).	cspec gnomad_v2 gnomad_v4
PM3	Not met	Not met: the exact variant was reported in a heterozygous proband, not with the VCEP-required homozygous FH phenotype and one qualifying variant in trans.	cspec PMID:16424354 PMID:19073363 gnomad_v4
PM4	N/A	Not applicable: p.(Cys231Gly) is a missense substitution, whereas the VCEP PM4 rule requires a qualifying in-frame deletion, insertion, or whole-exon duplication.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: a same-codon p.Cys231Arg report exists, but its pathogenic classification under these guidelines is not established.	cspec PMID:19073363 pm5_candidates
PM6	Not assessed	Not assessed: PS2-level de novo evidence is unavailable for the exact c.691T>G variant, so the VCEP's PM6 reference condition cannot be evaluated.	cspec PMID:11313767 PMID:16424354 PMID:19073363
PP1	Not assessed	Not assessed: no qualifying 2-3 informative meioses with an affected relative above the LDL-C 75th centile are documented for c.691T>G.	cspec PMID:10090473 PMID:10422804 PMID:11313767 PMID:16424354 PMID:19073363
PP2	N/A	Not applicable: the LDLR Familial Hypercholesterolemia VCEP explicitly excludes PP2 for this VCEP.	cspec
PP3	Met	Met: REVEL score 0.85 meets the VCEP PP3 missense threshold of ≥0.75 for Supporting evidence.	cspec revel
PP4	Not assessed	Not assessed: FH is reported, but validated diagnostic criteria and exclusion of alternative causes are not documented for the exact variant case.	cspec gnomad_v2 gnomad_v4 PMID:10422804 PMID:11313767 PMID:16424354
PP5	N/A	Not applicable: the LDLR FH VCEP explicitly prohibits PP5 use.	cspec
BA1	Not assessed	Not assessed: gnomAD reports a maximum observed frequency of 0.00574%, but the VCEP requires PopMax FAF ≥0.5%, which is unavailable.	cspec gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: gnomAD reports a maximum observed frequency of 0.00574%, but the VCEP requires PopMax FAF ≥0.2%, which is unavailable.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes but does not establish untreated, normolipidemic adult status or the required unrelated heterozygote count.	cspec gnomad_v2 gnomad_v4
BS3	Not met	Not met: the available report describes only 30–40% activity, not the VCEP's required >90% or >95% whole-cycle benign activity thresholds.	cspec clinvar PMID:10090473
BS4	Not assessed	Not assessed: two unrelated families with at least two informative meioses each and an unaffected carrier below the LDL-C 50th centile are not documented.	cspec PMID:16424354 PMID:19073363
BP1	N/A	Not applicable: the LDLR Familial Hypercholesterolemia VCEP explicitly excludes BP1 for this VCEP.	cspec
BP2	Not met	Not met: the heterozygous proband also carried PCSK9 R46L, but no pathogenic or likely pathogenic classification for that partner is documented.	cspec PMID:16424354
BP3	N/A	Not applicable: the VCEP excludes BP3 for this gene.	cspec
BP4	Not assessed	Not assessed: REVEL 0.85 exceeds the BP4 cutoff of ≤0.5, and the VCEP-required MaxEntScan splice result is unavailable.	cspec revel
BP5	N/A	Not applicable: the LDLR FH VCEP explicitly marks BP5 as not applicable.	cspec
BP6	N/A	Not applicable: the LDLR FH VCEP explicitly prohibits BP6 use.	cspec
BP7	N/A	Not applicable: c.691T>G is missense and produces p.(Cys231Gly), whereas the VCEP BP7 rule requires a synonymous variant.	cspec

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