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.734G>T (p.Gly245Val)

CA214324

36829 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 9df2dd82-e0b3-481a-8173-54a19387975f

HGVS expressions

NM_000545.8:c.734G>T

NM_000545.8(HNF1A):c.734G>T (p.Gly245Val)

NC_000012.12:g.120994184G>T

CM000674.2:g.120994184G>T

NC_000012.11:g.121431987G>T

CM000674.1:g.121431987G>T

NC_000012.10:g.119916370G>T

NG_011731.2:g.20439G>T

ENST00000257555.11:c.734G>T

ENST00000257555.10:c.734G>T

ENST00000400024.6:c.734G>T

ENST00000402929.5:n.869G>T

ENST00000535955.5:n.43-3307G>T

ENST00000538626.2:n.191-3307G>T

ENST00000538646.5:c.547G>T

ENST00000540108.1:c.*174G>T

ENST00000541395.5:c.734G>T

ENST00000541924.5:c.713+478G>T

ENST00000543427.5:c.633+558G>T

ENST00000544413.2:c.734G>T

ENST00000544574.5:c.73-2433G>T

ENST00000560968.5:n.877G>T

ENST00000615446.4:c.-257-2078G>T

ENST00000617366.4:c.586+605G>T

NM_000545.5:c.734G>T

NM_000545.6:c.734G>T

NM_001306179.1:c.734G>T

NM_001306179.2:c.734G>T

Uncertain Significance

PM1_Supporting PM2_Supporting PP3 PP4_Moderate

PM5

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.734G>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glycine to valine at codon 245 (p.Gly245Val) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative antibodies, and low hsCRP; HNF4A not tested, but low hsCRP is specific to HNF1A vs. HNF4A) (PP4_Moderate; PMID: 30181854). Another missense variant, c.733G>A (p.Gly245Arg) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.734G>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM1_Supporting, PM2_Supporting, PP3, PP4_Moderate.

PM1_Supporting

This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP.

PM2_Supporting

This variant is absent from gnomAD.

PP3

This variant is predicted deleterious by multiple lines of computational evidence with a REVEL score of 0.956.

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, antibody negative, and low hsCRP). While HNF4A was not tested, low hsCRP is highly specific to HNF1A vs. HNF4A (PMID: 30181854).

PM5

Another missense variant, c.733G>A (p.Gly245Arg) has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

Approved on: 2022-05-02

Published on: 2022-05-02

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