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.1135C>G (p.Pro379Ala)

CA6831955

431970 (ClinVar)

Gene: HNF1A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
UUID: 2e13c2de-6b67-4738-b89f-f88858c71a3b
Approved on: 2023-09-06
Published on: 2023-09-06

HGVS expressions

NM_000545.8:c.1135C>G
NM_000545.8(HNF1A):c.1135C>G (p.Pro379Ala)
NC_000012.12:g.120996568C>G
CM000674.2:g.120996568C>G
NC_000012.11:g.121434371C>G
CM000674.1:g.121434371C>G
NC_000012.10:g.119918754C>G
NG_011731.2:g.22823C>G
ENST00000257555.11:c.1135C>G
ENST00000257555.10:c.1135C>G
ENST00000400024.6:c.1135C>G
ENST00000402929.5:n.1270C>G
ENST00000535955.5:n.43-923C>G
ENST00000538626.2:n.191-923C>G
ENST00000538646.5:c.*111C>G
ENST00000540108.1:c.*575C>G
ENST00000541395.5:c.1135C>G
ENST00000541924.5:c.*149C>G
ENST00000543255.1:n.179C>G
ENST00000543427.5:c.634-36C>G
ENST00000544413.2:c.1135C>G
ENST00000544574.5:c.73-49C>G
ENST00000560968.5:n.952C>G
ENST00000615446.4:c.-78C>G
ENST00000617366.4:c.587-1066C>G
NM_000545.5:c.1135C>G
NM_000545.6:c.1135C>G
NM_001306179.1:c.1135C>G
NM_001306179.2:c.1135C>G
More

Benign

Met criteria codes 2
BA1 PP3
Not Met criteria codes 4
BP5 PS4 PM2 PM1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.2

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.1135C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to alanine at codon 379 (p.(Pro379Ala)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9639, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While this variant has been identified in >20 unrelated individuals with diabetes in the literature (ClinVar ID 431970, PMID:18003757, PMID: 23348805, PMID: 29207974, PMID: 21761282, PMID: 23607861), it has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0005091, which is greater than the MDEP threshold for BA1 (greater than 0.0001) (BA1). Therefore, PS4 cannot be applied. While another variant at this codon, c.1136C>G (p.(Pro379Arg)), is classified as Pathogenic by the MDEP, the c.1135C>G meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.1, approved 8/11/2023): BA1, PP3. It may, however, confer an increased risk of type 2 diabetes (OR = 11.8, p = 0.0007324 at type2diabetesgenetics.org).
Met criteria codes
BA1
This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of .000509, which is greater than the MDEP threshold for BA1 (greater than 0.0001) (BA1).
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9639, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
Not Met criteria codes
BP5
Identified in a case with HNF4A R114W, which has not been classified as a causal monogenic diabetes variant.
PS4
This variant was identified in >20 unrelated individuals with diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (ClinVar ID 431970, PMID:18003757, PMID: 23348805, PMID: 29207974, PMID: 21761282, PMID: 23607861, internal laboratory collaborators).
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.