12-120993663-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_ModeratePP3PM2_SupportingPP1_StrongPM1

This summary comes from the ClinGen Evidence Repository: The c.670C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 224 (p.(Pro224Ser)) of NM_000545.8. This variant segregated with diabetes, with four informative meioses in three families with MODY (PP1_Strong; PMID:15031772, internal lab contributors) and this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.944, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). Additionally, this variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Lastly, the c.670C>T variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.670C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved June 4, 2021): PP1_Strong, PP3, PP4_Moderate, PM1_Supporting, PM2_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA214317/MONDO:0015967/017

Frequency

Genomes: not found (cov: 32)

Consequence

HNF1A
NM_000545.8 missense

Scores

14
3
1

Clinical Significance

Likely pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 7.43
Variant links:
Genes affected
HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 10 ACMG points.

PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HNF1ANM_000545.8 linkc.670C>T p.Pro224Ser missense_variant Exon 3 of 10 ENST00000257555.11 NP_000536.6 P20823E0YMI7
HNF1ANM_001306179.2 linkc.670C>T p.Pro224Ser missense_variant Exon 3 of 10 NP_001293108.2 P20823E0YMI7
HNF1ANM_001406915.1 linkc.670C>T p.Pro224Ser missense_variant Exon 3 of 9 NP_001393844.1
HNF1AXM_024449168.2 linkc.670C>T p.Pro224Ser missense_variant Exon 3 of 9 XP_024304936.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HNF1AENST00000257555.11 linkc.670C>T p.Pro224Ser missense_variant Exon 3 of 10 1 NM_000545.8 ENSP00000257555.5 A0A0A0MQU7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Monogenic diabetes Pathogenic:1
Likely pathogenic, reviewed by expert panelcurationClinGen Monogenic Diabetes Variant Curation Expert PanelDec 30, 2021The c.670C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to serine at codon 224 (p.(Pro224Ser)) of NM_000545.8. This variant segregated with diabetes, with four informative meioses in three families with MODY (PP1_Strong; PMID: 15031772, internal lab contributors) and this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.944, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). Additionally, this variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Lastly, the c.670C>T variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.670C>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved June 4, 2021): PP1_Strong, PP3, PP4_Moderate, PM1_Supporting, PM2_Supporting -
Maturity onset diabetes mellitus in young Pathogenic:1
Likely risk allele, criteria provided, single submitterresearchClinical Genomics, Uppaluri K&H Personalized Medicine Clinic-Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs193922600 with MODY3. -
Maturity-onset diabetes of the young type 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testing;curationWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 18, 2011- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.93
.;D;D;.
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
1.0
D;D;D;D
M_CAP
Pathogenic
0.85
D
MetaRNN
Pathogenic
0.91
D;D;D;D
MetaSVM
Pathogenic
1.1
D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-6.2
D;.;D;D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.0010
D;.;D;D
Sift4G
Uncertain
0.0080
D;D;D;D
Polyphen
0.98
.;.;.;D
Vest4
0.75
MutPred
0.63
Gain of phosphorylation at P224 (P = 0.0396);Gain of phosphorylation at P224 (P = 0.0396);Gain of phosphorylation at P224 (P = 0.0396);Gain of phosphorylation at P224 (P = 0.0396);
MVP
0.99
MPC
1.9
ClinPred
1.0
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs193922600; hg19: chr12-121431466; API