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]

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Variant: NM_175914.5(HNF4A):c.1177G>A (p.Gly393Arg)

CA9870495

435440 (ClinVar)

Gene: HNF4A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 4d775106-7b61-4d80-b19c-a4156dc7c7fa

Approved on: 2023-05-27

Published on: 2023-05-27

HGVS expressions

NM_175914.5:c.1177G>A

NM_175914.5(HNF4A):c.1177G>A (p.Gly393Arg)

NC_000020.11:g.44428448G>A

CM000682.2:g.44428448G>A

NC_000020.10:g.43057088G>A

CM000682.1:g.43057088G>A

NC_000020.9:g.42490502G>A

NG_009818.1:g.77648G>A

ENST00000316099.10:c.1243G>A

ENST00000316099.9:c.1243G>A

ENST00000316099.8:c.1243G>A

ENST00000316673.8:c.1177G>A

ENST00000372920.1:c.*1010G>A

ENST00000415691.2:c.1243G>A

ENST00000457232.5:c.1177G>A

ENST00000619550.4:c.1168G>A

NM_000457.4:c.1243G>A

NM_001030003.2:c.1177G>A

NM_001258355.1:c.1222G>A

NM_001287182.1:c.1168G>A

NM_001287183.1:c.1168G>A

NM_175914.4:c.1177G>A

NM_178849.2:c.1243G>A

NM_001030003.3:c.1177G>A

NM_001258355.2:c.1222G>A

NM_001287182.2:c.1168G>A

NM_178849.3:c.1243G>A

NM_000457.5:c.1243G>A

NM_000457.6:c.1243G>A

NM_001287183.2:c.1168G>A

Benign

BS1 BS2

BP4 PS4 PP4 PP3 PM1 PM5

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF4A Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1177G>A in the HNF4A gene causes an amino acid change of glycine to arginine at codon 393 (p.Gly393Arg) of NM_15914.4. The nucleotide change c.1177G>C, which causes the same amino acid change, has been reported in a patient with monogenic diabetes; however, the c.1177G>C variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant is outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 37-113, 180-220 and 300-350). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0000751, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF4A-MODY is 95% by age 70 (internal lab contributor) (BS2). This variant has a REVEL score of 0.451, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on protein function. This variant was identified in individuals with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 and lack of clinical information (internal lab contributors). In summary, c.1177G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): BS1, BS2.

BS1

This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0000751, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1).

BS2

This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF4A-MODY is 95% by age 70 (internal lab contributor) (BS2).

BP4

This variant has a REVEL score of 0.451, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on protein function.

PS4

This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors).

PP4

This variant was identified in individuals with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 and lack of clinical information (internal lab contributors).

PP3

This variant has a REVEL score of 0.451, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on protein function.

PM1

This variant is outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 37-113, 180-220 and 300-350).

PM5

The nucleotide change c.1177G>C, which causes the same amino acid change, has been reported in a patient with monogenic diabetes; however, the c.1177G>C variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP.

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