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_000545.8(HNF1A):c.185A>G (p.Asn62Ser)

CA6831682

447485 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 7e62708e-dd55-42f5-9e0a-e6bdb1c0b199

Approved on: 2022-06-03

Published on: 2022-06-03

HGVS expressions

NM_000545.8:c.185A>G

NM_000545.8(HNF1A):c.185A>G (p.Asn62Ser)

NC_000012.12:g.120978953A>G

CM000674.2:g.120978953A>G

NC_000012.11:g.121416756A>G

CM000674.1:g.121416756A>G

NC_000012.10:g.119901139A>G

NG_011731.2:g.5208A>G

ENST00000257555.11:c.185A>G

ENST00000257555.10:c.185A>G

ENST00000400024.6:c.185A>G

ENST00000402929.5:n.320A>G

ENST00000535955.5:n.42+261A>G

ENST00000538626.2:n.190+113A>G

ENST00000538646.5:c.185A>G

ENST00000540108.1:c.185A>G

ENST00000541395.5:c.185A>G

ENST00000541924.5:c.185A>G

ENST00000543427.5:c.185A>G

ENST00000544413.2:c.185A>G

ENST00000544574.5:c.72+113A>G

ENST00000560968.5:n.328A>G

ENST00000615446.4:c.-258+242A>G

ENST00000617366.4:c.185A>G

NM_000545.5:c.185A>G

NM_000545.6:c.185A>G

NM_001306179.1:c.185A>G

NM_001306179.2:c.185A>G

Benign

BA1 BP5

BS3 PP4 PP3 PM1

Evidence Links 1

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.185A>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of asparagine to serine at codon 62 (p.(Asn62Ser)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00019, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). Furthermore, this variant was identified in a patient with an alternate molecular basis for disease (BP5; internal lab contributors). In summary, c.185A>G 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 9/30/21): BA1, BP5.

BA1

This variant has a gnomAD Popmax filtering AF greater than 0.0001 (actual value: 0.0001278) for European non-Finnish exomes.

BP5

This variant was present in one individual with GCK-MODY and one individual with hyperinsulinemia caused by an ABCC8 loss of function variant who developed diabetes post-partial pancreatectomy.

BS3

Najimi et al. reported that N62S HNF1A has 65% transcriptional activity and 70% of nuclear localization of wild type HNF1A.

Figure 2 showed and table 1 summarized that N62S HNF1A has 65% transcriptional activity of wild type HNF1A. Figure 3 showed and table 1 summarized that N62S HNF1A has 70% of nuclear location of wild type HNF1A. (HZ 11/4/18) PubMed:27899486

PP4

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

PP3

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

PM1

Not within DNA binding or dimerization domains.

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