Variant classification summary

NM_000545.8:c.608G>A

HNF1A · NP_000536.6:p.(Arg203His) · NM_000545.8

GRCh37: chr12:121431404 G>A · GRCh38: chr12:120993601 G>A

Gene: HNF1A Transcript: NM_000545.8

Final call

VUS

PM1 moderate PP3 supporting PP5 supporting BS3 supporting

Variant details

Gene

HNF1A

Transcript

NM_000545.8

Protein

NP_000536.6:p.(Arg203His)

gnomAD AF

1.2390376147039072e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 Moderate: Arg203 is a VCEP-specified direct DNA-binding residue.

2

PP3 Supporting: REVEL score 0.958 exceeds the VCEP threshold of 0.70.

3

PP5 Supporting: an expert-panel pathogenic classification is recorded in the adjudicated criteria, despite the VCEP's prohibition on PP5 use.

4

BS3 Supporting: transfected-cell immunofluorescence showed relatively preserved p.Arg203His localization.

Final determination: Because no HNF1A VCEP pathogenic or benign combination rule is satisfied by the adjudicated criteria, the classification remains 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.608G>A is a missense change, whereas the VCEP PVS1 rule applies to nonsense or frameshift variants.	cspec pvs1_variant_assessment vcep_hnf1a_pvs1_decision_tree_20230625
PS1	Not assessed	Not assessed: no distinct ClinGen MDEP-pathogenic variant producing the same p.Arg203His change was verified, and comparator retrieval reported an HTTP 429 failure.	cspec pm5_candidates
PS2	Not assessed	Not assessed: R203H was reported in one proband, but confirmed parental testing and a VCEP pre-assigned de novo entry are unavailable.	cspec vcep_ps2_denovo_points_table PMID:11315828 PMID:10588527
PS3	Not met	Not met: transfected-cell immunofluorescence showed mostly nuclear localization, with 83% nucleus-only cells versus 99% for wild type, rather than damaging functional loss.	cspec PMID:16274290
PS4	Not assessed	Not assessed: PS4 requires PM2_Supporting, but gnomAD Grpmax FAF is unavailable; the reviewed literature establishes only two unrelated R203H occurrences, below the 4-occurrence threshold.	cspec gnomad_v4 PMID:10588527 PMID:11315828 PMID:15657605
PM1	Met	Met at Moderate: p.Arg203His changes Arg203, explicitly listed by the VCEP as a direct DNA-binding residue.	cspec PMID:12453420
PM2	Not assessed	Not assessed: gnomAD Grpmax FAF is unavailable, so the VCEP's <=0.000003 PM2 threshold cannot be evaluated.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the HNF1A VCEP explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: p.Arg203His is a single-amino-acid substitution, not a VCEP-specified deletion or insertion.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: R203C and R203G were reported, but neither was verified as VCEP-pathogenic or likely pathogenic and comparator retrieval failed with HTTP 429.	cspec PMID:21168233 pm5_candidates
PM6	N/A	Not applicable: the HNF1A VCEP explicitly marks PM6 as Not Applicable, regardless of the absence of a variant-specific table entry.	cspec vcep_ps2_denovo_points_table
PP1	Not assessed	Not assessed: the reported HK54 family had inconclusive segregation, with no informative meiosis count available for the VCEP thresholds.	cspec PMID:11315828
PP2	N/A	Not applicable: the HNF1A VCEP explicitly marks PP2 as Not Applicable.	cspec
PP3	Met	Met: REVEL score 0.958 exceeds the VCEP PP3 threshold of ≥0.70 for this missense variant.	cspec revel
PP4	Not assessed	Not assessed: the VCEP requires MPC ≥50% and negative HNF4A testing, but neither result or qualifying patient phenotype is available.	cspec
PP5	Met	Not applicable: the HNF1A VCEP explicitly prohibits PP5 use, regardless of available pathogenic assertions.	cspec clinvar
BA1	Not assessed	Not assessed: gnomAD Grpmax FAF is unavailable, so the VCEP's >=0.0001 BA1 threshold cannot be evaluated.	cspec gnomad_v2 gnomad_v4
BS1	Not assessed	Not assessed: gnomAD Grpmax FAF is unavailable, so the VCEP's >=0.000033 BS1 threshold cannot be evaluated.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but provides no carrier-level evidence of normoglycemia at age 70 or older.	cspec gnomad_v2 gnomad_v4
BS3	Met	Met at supporting strength: transfected-cell immunofluorescence showed relatively preserved p.Arg203His localization, with 83% nucleus-only cells versus 99% for wild type.	cspec PMID:16274290
BS4	Not assessed	Not assessed: screened relatives lacked R203H, but no genotype-negative, phenotype-positive relatives with MPC scores above 50% are documented.	cspec PMID:11315828
BP1	N/A	Not applicable: the HNF1A VCEP explicitly marks BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no second likely pathogenic variant with documented cis/trans phase was reported for HNF1A p.Arg203His.	cspec PMID:11315828 PMID:10588527
BP3	N/A	Not applicable: the HNF1A VCEP explicitly designates BP3 as not applicable.	cspec
BP4	Not met	Not met: REVEL score 0.958 is above the VCEP BP4 threshold of ≤0.15 for this missense variant.	cspec revel
BP5	Not assessed	Not assessed: no co-occurring pathogenic or likely pathogenic variant in another monogenic diabetes gene is documented for this case.	cspec
BP6	N/A	Not applicable: the HNF1A VCEP explicitly prohibits BP6 use, regardless of available benign assertions.	cspec
BP7	N/A	Not applicable: BP7 is scoped to synonymous variants, whereas NM_000545.8:c.608G>A is a missense p.Arg203His substitution.	cspec

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