Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_000545.8(HNF1A):c.871C>T (p.Pro291Ser)

CA6831856

447505 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 39100506-3321-43d5-83a7-952b8a81b5ef

HGVS expressions

NM_000545.8:c.871C>T

NM_000545.8(HNF1A):c.871C>T (p.Pro291Ser)

NC_000012.12:g.120994321C>T

CM000674.2:g.120994321C>T

NC_000012.11:g.121432124C>T

CM000674.1:g.121432124C>T

NC_000012.10:g.119916507C>T

NG_011731.2:g.20576C>T

ENST00000257555.11:c.871C>T

ENST00000257555.10:c.871C>T

ENST00000400024.6:c.871C>T

ENST00000402929.5:n.1006C>T

ENST00000535955.5:n.43-3170C>T

ENST00000538626.2:n.191-3170C>T

ENST00000538646.5:c.684C>T

ENST00000540108.1:c.*311C>T

ENST00000541395.5:c.871C>T

ENST00000541924.5:c.713+615C>T

ENST00000543427.5:c.633+695C>T

ENST00000544413.2:c.871C>T

ENST00000544574.5:c.73-2296C>T

ENST00000560968.5:n.893+121C>T

ENST00000615446.4:c.-257-1941C>T

ENST00000617366.4:c.586+742C>T

NM_000545.5:c.871C>T

NM_000545.6:c.871C>T

NM_001306179.1:c.871C>T

NM_001306179.2:c.871C>T

Likely Benign

BS1 BP2 BS3_Supporting

BS2 BP5 PS4 PP1 PP3 PM5 PM1

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.871C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 291 (p.(Pro291Ser)) of NM_000545.8. • This variant has been observed in unknown phase with the variant c.494G>A, p.Trp165Ter (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2). Functional studies demonstrated the p.Pro291Ser protein has abnormal nuclear localization above 75% of wildtype, indicating that this variant does not impact protein function (PMID: 32910913) (BS3_Supporting). Lastly, this variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00001163, which is greater than or equal to the MDEP threshold for BS1 (≥0.000033) (BS1). In summary, c.871C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/2021): BP2, BS3_Supporting, BS1

BS1

Popmax Filtering AF 0.00001163 (exomes) or 0.00002242 (genomes)

BP2

Seen in individual who also carries HNF1A p.Trp165Ter variant, which has been curated as pathogenic

BS3_Supporting

PMID: 32910913, Luciferase activity ~50% by Bergen group, 90-100% by Oxford group. Protein expression ~75% by Bergen group. ~1.75 fold change in expression by Oxford group. Nuclear localization ~75% WT by Bergen and Oxford groups. DNA binding ~same as WT (Oxford).

BS2

Seen in 6 normoglycemic individuals in large US biobank, but they are under 70 years old

BP5

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

3 cases

PP1

One meiosis in PMID: 20132997

PP3

REVEL = 0.56

PM5

Other variants at amino acid 291 are not pathogenic or likely pathogenic

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2022-04-21

Published on: 2022-04-21

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