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]

Variant: NM_000545.8(HNF1A):c.155_156delinsCT (p.Gly52Ala)

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Curation History
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CA159995

134503 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2abbfbc5-058c-45f2-b93f-1bb4d15351f1

Approved on: 2022-05-03

Published on: 2022-05-03

HGVS expressions

NM_000545.8:c.155_156delinsCT

NM_000545.8(HNF1A):c.155_156delinsCT (p.Gly52Ala)

NC_000012.12:g.120978923_120978924delinsCT

CM000674.2:g.120978923_120978924delinsCT

NC_000012.11:g.121416726_121416727delinsCT

CM000674.1:g.121416726_121416727delinsCT

NC_000012.10:g.119901109_119901110delinsCT

NG_011731.2:g.5178_5179delinsCT

ENST00000257555.11:c.155_156delinsCT

ENST00000257555.10:c.155_156delinsCT

ENST00000400024.6:c.155_156delinsCT

ENST00000402929.5:n.290_291delinsCT

ENST00000535955.5:n.42+231_42+232delinsCT

ENST00000538626.2:n.190+83_190+84delinsCT

ENST00000538646.5:c.155_156delinsCT

ENST00000540108.1:c.155_156delinsCT

ENST00000541395.5:c.155_156delinsCT

ENST00000541924.5:c.155_156delinsCT

ENST00000543427.5:c.155_156delinsCT

ENST00000544413.2:c.155_156delinsCT

ENST00000544574.5:c.72+83_72+84delinsCT

ENST00000560968.5:n.298_299delinsCT

ENST00000615446.4:c.-258+212_-258+213delinsCT

ENST00000617366.4:c.155_156delinsCT

NM_000545.5:c.155_156delinsCT

NM_000545.6:c.155_156delinsCT

NM_001306179.1:c.155_156delinsCT

NM_001306179.2:c.155_156delinsCT

Benign

BA1

PP1 PP3 PM2 PS4

Evidence Links 2

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.155_156delinsCT variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of Glycine to Alanine at codon 52 (p.(Gly52Ala)) of transcript NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0024, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). In summary, c.155_156delinsCT meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): BA1.

BA1

Both the c.155G>C and c.156C>T were identified in 73 alleles from the African population in gnomAD and appear to be in cis (on the same chromosome) in all occurrences. For both variants, the gnomAD exome Popmax Filtering AF is 0.0024 in the African population.

PP1

Elbein et al. (2000) reported Gly52Ala was present in 2 of 4 diabetic siblings and 1 nondiabetic sibling in a single family. The carrier is a 41-year-old woman with normal glucose tolerance.

"Gly52Ala was present in 2 of 4 diabetic siblings and 1 nondiabetic sibling in a single family. Surprisingly, this variant required changes in 2 adjacent nucleotides, neither of which is commonly altered. The presence of both nucleotide changes on the same allele was confirmed by sequencing cloned DNA. Although a lack of segregation with diabetes in the single family argues against a causative role for this mutation in diabetes, the glycine at this position is invariant in human, mouse, rat, and hamster. " "This variant is in a conserved region of HNFIct but was present in only 2 of 4 diabetic family members, was not present in an individual with impaired glucose tolerance, and was carried by a 41-year-old woman with normal glucose tolerance." (HZ 11/5/2018) PubMed:10690959

PP3

Missense predictive algorithms not in favor of impact; REVEL 0.313; MT, LRT, MA, SIFT, PROVEAN all predict benign. Weak Grantham's distance between Gly and Ala.

PM2

PS4

The variant was reported by Bennett JT et al. (2015) in one MODY patient from 331 suspected MODY, NDM, CHI probands. No other information available in the paper. Review article also cites unpublished data.

The variant was reported in one MODY patient from 331 suspected MODY, NDM, CHI probands. No other information available in the paper. (HZ 11/5/2018) PubMed:25555642

Curation History

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