Variant classification summary

NM_000545.6:c.341G>A

HNF1A · NP_000536.5:p.(Arg114His) · NM_000545.6

GRCh37: chr12:121426650 G>A · GRCh38: chr12:120988847 G>A

Gene: HNF1A Transcript: NM_000545.6

Final call

Likely Benign

PM1 supporting BS1 strong benign BS3 supporting benign

Variant details

Gene

HNF1A

Transcript

NM_000545.6

Protein

NP_000536.5:p.(Arg114His)

gnomAD AF

4.832414348553374e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000545.6:c.341G>A (p.Arg114His) is a missense variant in HNF1A, a gene in which loss-of-function variants cause autosomal dominant monogenic diabetes (MODY3).

2

This variant is present in gnomAD v2.1 at a grpmax filtering allele frequency of 9.374e-05 (14/282,682 alleles) and in gnomAD v4.1 at 4.428e-05 (78/1,614,100 alleles), exceeding the CSPEC BS1_Strong threshold of 1:30,000 (0.000033).

3

Functional characterization by Najmi et al. (2017) demonstrated that p.Arg114His retains 83% of wild-type transactivation activity in a luciferase reporter assay and shows normal nuclear localization (81%), meeting the CSPEC BS3_Supporting threshold of ≥75% activity.

4

The variant is located at codon 114, which lies within the CSPEC-defined DNA binding domain subset (codons 107-174), supporting application of PM1_Supporting. However, Arg114 is not among the directly DNA-binding residues specified for PM1_Moderate.

5

In silico predictions are indeterminate: REVEL score is 0.58 (below the CSPEC PP3 threshold of 0.70; above the BP4 threshold of 0.15); SpliceAI predicts no splicing impact (max delta 0.01).

6

The variant has been reported in ClinVar as Uncertain significance by 5 clinical laboratories and Likely benign by 1 laboratory (VariationID: 134508). No expert panel classification is available.

7

Applying the CSPEC v3.1.0 combination rules: BS1 (Strong Benign) and BS3 (Supporting Benign) are met on the benign side, while PM1 (Supporting Pathogenic) is met on the pathogenic side. Per Rule 24 (≥1 Benign Strong + ≥1 Pathogenic Supporting), the evidence is conflicting, resulting in a classification of Uncertain Significance.

Final determination: Rule18 in the ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 3.1.0 v3.1.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

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	PVS1 applies only to null variants (nonsense, frameshift, canonical splice sites, initiation codon, exon deletions). c.341G>A is a missense variant (p.Arg114His) and does not fall into any PVS1 null-variant bucket per the HNF1A CSPEC decision tree.
PS1	Not met	No previously classified pathogenic variant encoding the same amino acid change (p.Arg114His) has been identified. No same-residue pathogenic comparator is available in the CSPEC framework.
PS2	Not met	No de novo occurrence data are available for this variant. No proband with confirmed parental relationships has been reported in the reviewed literature.
PS3	Not met	CSPEC PS3_Supporting requires transactivation ≤40% of wild-type. The variant p.Arg114His demonstrated 83% transactivation activity in a luciferase reporter assay (PMID:27899486), which does not meet the threshold for damaging functional effect. CSPEC PS3_Moderate requires ≤40% transactivation by Gloyn/Oxford group; not applicable here.	PMID:27899486
PS4	Not met	CSPEC requires PM2_Supporting as a prerequisite for applying PS4 at any level. PM2 is not met (gnomAD grpmax FAF 9.374e-05 exceeds the 3.0e-06 threshold). Additionally, no systematic count of unrelated MODY probands with this variant is available in the reviewed evidence.	gnomad_v2
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 framework nor in the ClinGen Monogenic Diabetes CSPEC for HNF1A. No applicable rule exists.
PM1	Met	Codon 114 lies within the DNA binding domain subset (codons 107-174) defined by the HNF1A CSPEC for PM1_Supporting. The variant is not in the directly DNA-binding residue list for PM1_Moderate. Located in a statistically significant hotspot (evidence_brief).	cspec
PM2	Not met	CSPEC PM2_Supporting requires gnomAD grpmax FAF ≤ 1:333,000 (≤ 0.000003). The highest observed grpmax FAF is 9.374e-05 (gnomAD v2.1), which exceeds this threshold. The variant is present in population databases at a frequency inconsistent with PM2.	gnomad_v2 gnomad_v4
PM5	Not met	No previously classified pathogenic or likely pathogenic missense variants at residue Arg114 were identified. The pm5_candidates search returned 0 same-residue comparator variants. Without a pathogenic comparator at this residue, PM5 cannot be applied.
PM6	N/A	PM6 is subsumed by PS2 per CSPEC v3.1.0 and is not applicable for this VCEP. No assumed de novo evidence was reviewed.
PP1	Not met	No cosegregation data are available for this variant. No family studies with meiotic counts were identified in the reviewed literature.
PP2	N/A	PP2 is not applicable per CSPEC v3.1.0. The HNF1A gene constraint score (1.07) is not significant, and the CSPEC does not support using this criterion.	cspec
PP3	Not met	CSPEC PP3_Supporting requires REVEL score ≥ 0.70. The REVEL score for this variant is 0.58, which is below the threshold. SpliceAI max delta is 0.01, indicating no predicted splicing impact. BayesDel score is 0.007 (low). In silico tools do not support a deleterious prediction.	revel bayesdel spliceai
PP4	Not met	No patient-specific phenotype data are available for this adjudication. CSPEC PP4 requires MODY Probability Calculator score ≥ 50%, negative HNF4A testing, and additional HNF1A-MODY features. No such clinical data were provided or identified in the literature.
PP5	N/A	PP5 is not applicable for this VCEP per CSPEC v3.1.0. The ClinGen Sequence Variant Interpretation VCEP Review Committee does not support use of this criterion.	cspec
BA1	Not met	CSPEC BA1 requires gnomAD grpmax FAF ≥ 1:10,000 (≥ 0.0001). The highest observed grpmax FAF is 9.374e-05 (gnomAD v2.1), which is below the BA1 threshold. The variant is too rare in population databases to be considered a common polymorphism.	gnomad_v2 gnomad_v4
BS1	Met	CSPEC BS1_Strong requires gnomAD grpmax FAF ≥ 1:30,000 (≥ 0.000033). The variant has gnomAD v2.1 grpmax FAF of 9.374e-05, which exceeds this threshold by approximately 2.8-fold. This allele frequency is greater than expected for HNF1A-MODY, a rare monogenic disorder.	gnomad_v2 gnomad_v4
BS2	Not met	CSPEC BS2 requires observation in normoglycemic individuals aged 70 or older. No such data are available in the reviewed evidence. The population cohort data in PMID:27899486 included individuals from Framingham Heart Study and Jackson Heart Study, but age-specific normoglycemic status is not reported for this variant.
BS3	Met	CSPEC BS3_Supporting requires luciferase transactivation assay showing ≥ 75% of wild-type activity. In PMID:27899486 (Najmi et al. 2017), the p.Arg114His variant demonstrated 83% transactivation activity compared to wild-type in a validated luciferase reporter assay in transfected HeLa cells, with normal nuclear localization (81% of cells with nuclear accumulation). This meets the CSPEC threshold for benign functional evidence.	PMID:27899486
BS4	Not met	CSPEC BS4 applies to family members without the variant who have MPC score >50% (genotype-negative, phenotype-positive). No such segregation data are available for this variant.
BP1	N/A	BP1 is not applicable per CSPEC v3.1.0. This criterion (missense variant in gene where primarily truncating variants cause disease) is not supported by the HNF1A CSPEC.	cspec
BP2	Not met	No evidence that this variant has been observed in cis or in trans with a pathogenic or likely pathogenic HNF1A variant. No phase data available.
BP3	N/A	Not applicable: variant is a substitution, not an in-frame deletion/insertion in a repetitive region.
BP4	Not met	CSPEC BP4_Supporting requires REVEL score ≤ 0.15. The REVEL score for this variant is 0.58, which exceeds the threshold. SpliceAI max delta is 0.01, but this criterion is not applicable for BP4 on a missense variant per CSPEC guidance (BP4 SpliceAI rule is for non-canonical splicing and synonymous variants only).	revel
BP5	Not met	No evidence that a pathogenic or likely pathogenic variant in an alternative monogenic diabetes gene has been identified in a proband carrying this variant.
BP6	N/A	BP6 is not applicable for this VCEP per CSPEC v3.1.0. The ClinGen Sequence Variant Interpretation VCEP Review Committee does not support use of this criterion.	cspec
BP7	N/A	BP7 applies to synonymous variants with SpliceAI delta < 0.2 and phyloP < 2.0. This variant is a missense substitution (c.341G>A, p.Arg114His), not a synonymous variant, and is therefore not eligible for BP7.

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