Variant classification summary

NM_006446.5:c.521T>C

SLCO1B1 · NP_006437.3:p.(Val174Ala) · NM_006446.5

GRCh37: chr12:21331549 T>C · GRCh38: chr12:21178615 T>C

Gene: SLCO1B1 Transcript: NM_006446.5

Final call

Benign

BA1 stand-alone benign BS1 strong BP4 supporting

Variant details

Gene

SLCO1B1

Transcript

NM_006446.5

Protein

NP_006437.3:p.(Val174Ala)

gnomAD AF

0.1422902706314068 (v4.1)

ClinVar

drug response

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Benign: BA1 stand-alone benign is met by gnomAD v4.1 grpmax FAF of 0.195837, above 0.05.

2

Benign: BS1 strong is met by gnomAD v4.1 grpmax FAF of 0.195837, above 0.01.

3

Benign: BP4 supporting is met because REVEL 0.221 is at or below the 0.29 threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, BA1 alone is sufficient for a Benign classification; BS1 and BP4 are additional benign evidence.

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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: p.Val174Ala is reported for drug response, but no previously established pathogenic variant with the same amino-acid change is documented.	clinvar PMID:19833260 PMID:21243006 PMID:26086347 PMID:28940218
PS2	Not assessed	Not assessed: no documented disease proband with confirmed maternity and paternity testing or a stated absence of family history.
PS3	Not assessed	Not assessed: reviewed reports provide clinical or pharmacokinetic associations, but no auditable primary functional assay result with controls establishes a damaging effect.	PMID:21243006 PMID:19833260 PMID:28940218 PMID:26086347 PMID:23942138
PS4	Not met	Not met: the strongest reported case-control odds ratio was 4.47, below the ACMG/AMP PS4 requirement of OR >5.0 with confidence interval excluding 1.0.	PMID:19833260 PMID:21243006 PMID:23942138 PMID:26086347 PMID:27595674 PMID:28940218
PM1	Not met	Not met: residue 174 has no documented critical-domain or permitted hotspot designation, and cancerhotspots.org returned no significant SLCO1B1 V174 hotspot.	hotspots
PM2	Not met	Not met: gnomAD v4.1 allele frequency is 0.142290, vastly exceeding the PM2 supporting threshold of 0.0001.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no pathogenic partner variant or parental/offspring testing establishes NM_006446.5:c.521T>C in trans.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no verified pathogenic alternate missense change at Val174 is available for comparison.	pm5_candidates
PM6	Not assessed	Not assessed: no documented de novo disease case or parental testing showing the variant was absent without maternity and paternity confirmation.
PP1	Not assessed	Not assessed: no affected family members with variant genotypes or co-segregation data are reported for the disease context.
PP2	Not met	Not met: gnomAD v4.1 shows p.Val174Ala at AF 0.142290 with 17,896 homozygotes, contradicting a low rate of benign missense variation.	gnomad_v4 gnomad_v2
PP3	Not met	Not met: REVEL 0.221 is below the >=0.644 generic PP3 supporting threshold for missense variants.	revel
PP4	Not met	Not met: statin-associated muscle symptoms are treatment-related and multifactorial, not highly specific for a disease with a single genetic etiology.	PMID:19833260 PMID:21243006 PMID:23942138 PMID:26086347 PMID:27595674 PMID:28940218
PP5	Not met	Not met: no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification was identified for this variant.	clinvar
BA1	Met	Met: gnomAD v4.1 grpmax FAF is 0.195837, exceeding the BA1 threshold of 0.05 in a population with 63,968 observed alleles.	gnomad_v4 gnomad_v2
BS1	Met	Met: gnomAD v4.1 grpmax FAF is 0.195837, far above the generic BS1 threshold of 0.01 with 63,968 Finnish observed alleles.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: gnomAD reports 17,896 homozygotes, but population records do not establish healthy-adult status, phenotype, age, or full penetrance.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: available studies report clinical or pharmacokinetic associations, not a well-established functional result demonstrating no damaging effect on protein function or splicing.	PMID:21243006 PMID:19833260 PMID:28940218 PMID:26086347 PMID:23942138
BS4	Not assessed	Not assessed: no affected relatives with variant genotypes are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: the supplied evidence does not show that SLCO1B1 disease is primarily caused by truncating variants.
BP2	Not assessed	Not assessed: no family or proband data establish the variant in trans or cis with a pathogenic allele.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met, supporting: REVEL 0.221 is at or below the <=0.29 generic BP4 supporting threshold for missense variants.	revel
BP5	Not assessed	Not assessed: the available evidence does not establish an alternate molecular basis in a case carrying this variant.
BP6	Not met	Not met: benign and likely-benign laboratory submissions exist, but no exact-variant expert-panel Benign or Likely benign classification qualifies for BP6.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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