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.1522G>A (p.Glu508Lys)

CA289173

135665 (ClinVar)

Gene: HNF1A
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
UUID: 0285392d-14d0-41c7-8b20-aabbdacbd554
Approved on: 2022-12-01
Published on: 2022-12-01

HGVS expressions

NM_000545.8:c.1522G>A
NM_000545.8(HNF1A):c.1522G>A (p.Glu508Lys)
NC_000012.12:g.120999288G>A
CM000674.2:g.120999288G>A
NC_000012.11:g.121437091G>A
CM000674.1:g.121437091G>A
NC_000012.10:g.119921474G>A
NG_011731.2:g.25543G>A
ENST00000257555.11:c.1522G>A
ENST00000257555.10:c.1522G>A
ENST00000540108.1:c.*962G>A
ENST00000541395.5:c.1522G>A
ENST00000543427.5:c.985G>A
ENST00000544413.2:c.1522G>A
ENST00000560968.5:n.1339G>A
ENST00000615446.4:c.310G>A
ENST00000617366.4:c.639G>A
NM_000545.5:c.1522G>A
NM_000545.6:c.1522G>A
NM_001306179.1:c.1522G>A
NM_001306179.2:c.1522G>A
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Benign

Met criteria codes 1
BA1
Not Met criteria codes 2
PS3 PS4

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.1522G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to lysine at codon 508 (p.(Glu508Lys)) of transcript NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.002884, which is greater than the MDEP threshold for BA1 (greater than or equal to 0.0001) (BA1). This variant has been found in many unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes (PMID: 24915262); however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting. Functional studies demonstrated the p.Glu508Lys protein has transactivation activity between 40-80%, which is less severe than typical HNF1A-MODY-causing variants (below 40%) (PMID: 32910913, 27899486). In summary, this variant meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP: BA1 (specification version 1.2, approved 6/5/21). However, this variant is an established risk allele for type 2 diabetes in individuals of Mexican ancestry (PMID: 24915262). These individuals do not respond to treatment with sulfonylureas, unlike individuals with HNF1A-MODY (PMID: 29844095).
Met criteria codes
BA1
This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.002884, which is greater than the MDEP threshold for BA1 (greater than or equal to 0.0001).
Not Met criteria codes
PS3
Functional studies demonstrated the p.Glu508Lys protein has transactivation activity between 40-80%, which is less severe than typical HNF1A-MODY-causing variants (below 40%) (PMID: 32910913, 27899486).
PS4
This variant has been found in many unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes (PMID: 24915262); however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting.
Curation History
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