NM_001306179.2:c.-218T>C

CA244520160

1327603 (ClinVar)

Gene: HNF1A

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

UUID: 7e674cec-857b-4138-8600-528cf53d76ea

Approved on: 2021-12-08

Published on: 2022-02-25

HGVS expressions

NM_001306179.2:c.-218T>C
NC_000012.12:g.120978551T>C
CM000674.2:g.120978551T>C
NC_000012.11:g.121416354T>C
CM000674.1:g.121416354T>C
NC_000012.10:g.119900737T>C
NG_011731.2:g.4806T>C
ENST00000257555.11:c.-218T>C
ENST00000257555.10:c.-218T>C
NM_000545.8:c.-218T>C
NM_000545.8(HNF1A):c.-218T>C

Uncertain Significance

• Met criteria codes: PP4_Moderate PM1_Supporting

• Not Met criteria codes: PS3 PS4 PM2 BS3

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.-218T>C variant in the HNF1 homeobox 1 gene, HNF1A gene, is a single nucleotide variant within the promoter region of NM_000545.8. This variant is located within the overlapping HNF3 and NF-Y sites (c.-209 to c.-227) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (internal lab contributors); however, PS4 cannot be applied because the frequency of the c.-218T>C variant is 0.0000319 in gnomAD v2.1.1, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither PM2_Supporting, BS1, nor PS4_moderate can be applied. Additionally, functional studies demonstrated the variant has transactivation activity at 70% of wildtype, suggesting that this variant does not impact protein function, however sufficient controls were not used per MDEP guidelines and therefore BS3 cannot be applied (PMID: 10649494). Taken together, this evidence supports the classification of this variant as a variant of uncertain significance. ACMP/AMP criteria applied, as specified by the ClinGen MDEP VCEP: PM1_Supporting, PP4_Moderate (specification version 1.0).

Met criteria codes

• PP4_Moderate: One of the above individuals has a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea responsive) (PP4_Moderate; internal lab contributor).
• PM1_Supporting: This variant is located within the overlapping HNF3 and NF-Y sites (c.-209 to c.-227) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting).

Not Met criteria codes

• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: This variant was identified in five unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (internal lab contributors).
• PM2: The frequency of the c.-218T>C variant is 0.0000319 in gnomAD v2.1.1 is , which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.
• BS3: Functional studies demonstrated the variant has transactivation activity at 70% of wildtype, suggesting that this variant does not impact protein function, however sufficient controls were not used per MDEP guidelines and therefore BS3 cannot be applied(PMID: 10649494).