rs754729248

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PP1_StrongBS1PM5_SupportingPP3PP4

This summary comes from the ClinGen Evidence Repository: The c.1136C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 379 (p.(Pro379Thr)) of NM_000545.6. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003898, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in 13 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 (PMIDs 21170474, 15657605, internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a MODY probability calculator result >50% and negative genetic testing for HNF4A (PP4; internal lab contributor). This variant segregated with diabetes, with at least 4 informative meioses in 3 families (PP1_Strong; internal lab contributors). Another missense variant, c.1136C>G p.Pro379Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Pro379Thr (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS1, PP3, PP4, PP1_Strong, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831957/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

12

4

2

Clinical Significance

Uncertain significance reviewed by expert panel P:5U:4

Conservation

PhyloP100: 7.89

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]

HNF1A links:

HNF1A (HGNC:):

HNF1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM5

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.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8 linkuse as main transcript	c.1135C>A	p.Pro379Thr	missense_variant	6/10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 linkuse as main transcript	c.1135C>A	p.Pro379Thr	missense_variant	6/10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 linkuse as main transcript	c.1135C>A	p.Pro379Thr	missense_variant	6/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.1135C>A	p.Pro379Thr	missense_variant	6/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.1135C>A	p.Pro379Thr	missense_variant	6/10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

5

AN:

152172

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000240

AC:

6

AN:

250080

Hom.:

0

AF XY:

0.0000148

AC XY:

2

AN XY:

135380

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

26

AN:

1461638

Hom.:

0

Cov.:

36

AF XY:

0.0000165

AC XY:

12

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

5

AN:

152172

Hom.:

0

Cov.:

32

AF XY:

0.0000538

AC XY:

4

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000251

Hom.:

0

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

3

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:5Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 379 of the HNF1A protein (p.Pro379Thr). This variant is present in population databases (rs754729248, gnomAD 0.01%). This missense change has been observed in individuals with maturity-onset diabetes of the young (PMID: 18003757, 21683639, 22808921, 23348805, 23803251, 25935773, 26479152, 28012402, 28170077, 30293189). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 972818). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1A protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 22, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene and appears to segregate with disease in multiple families (personal communication from ClinGen Monogenic Diabetes Expert Panel). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32910913, 18003757, 21224407, 28170077, 23348805, 36208343, 34108472, 28012402, 21683639, 16917892, 26479152, 15883474, 15657605, 36208030, 30293189) -

Maturity-onset diabetes of the young type 3

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Pro379Thr variant in HNF1A has been reported in 10 individuals with maturity-onset diabetes of the young, segregated with disease in 9 affected relatives from 3 families (PMID: 30293189, 21683639, 26479152, 28012402), and has been identified in 0.011% (4/35382) of Latino chromosomes and 0.002% (3/128426) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754729248). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Pro379Thr have been reported in association with disease in the literature (PMID: 23348805, 16917892). Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Pro379Arg and p.Pro379His, have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 23348805, 16917892, 29666556, 15657605, 23348805, 16917892, 15883474). In summary, this variant meets criteria to be classified as pathogenic for maturity-onset diabetes of the young in an autosomal dominant manner based on segregation with disease, location in a mutation hotspot, and two likely pathogenic variants that affect the same amino acid. ACMG/AMP Criteria applied: PP1_Strong, PM1, PM5, PP3, PS4_Supporting (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:18003757,18003757,15883474,15657605). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.967>=0.6). A missense variant is a common mechanism . Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Maturity onset diabetes mellitus in young

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 06, 2020

The p.Pro379Thr variant in HNF1A has been reported in at least 10 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in at least 6 affected relatives from 3 families (Wang 2019 PMID: 30293189, Kyithar 2011 21683639, Bacon 2016 26479152, Giuffrida 2017 28012402, Santana 2017 PMID: 28170077, Bellanné-Chantelot 2008 PMID: 18003757). It has been identified in 0.011% (4/35382) of Latino chromosomes and 0.002% (3/128426) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Pro379 codon is one of the most frequently mutated sites in the HNF1A gene (Ellard and Colclough 2013 PMID: 23348805). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PP1_Moderate, PM1, PP3, PS4_Moderate. -

HNF1A-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2024

The HNF1A c.1135C>A variant is predicted to result in the amino acid substitution p.Pro379Thr. This variant has been reported to be causative for maturity onset diabetes of the young (MODY) (Bellanne-Chantelot et al. 2008. PubMed ID: 18003757; Wang et al. 2018. PubMed ID: 30293189; Goodrich et al. 2021. PubMed ID: 34108472. Supp Data 5). Of note, Goodrich et al. showed that this variant may have reduced penetrance. In addition, different missense substitutions at the same codon (p.Pro379Ala, p.Pro379Ser, Pro379His, Pro379Arg) have also been reported to be pathogenic for MODY (Dominguez-Lopez et al. 2005. PubMed ID: 15883474; Xu et al. 2005. PubMed ID: 15657605; Bellanne-Chantelot et al. 2008. PubMed ID: 18003757; Ekholm et al. 2013. PubMed ID: 23607861). Therefore, we classify the c.1135C>A (p.Pro379Thr) variant in this patient as pathogenic. -

Monogenic diabetes

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Aug 14, 2023

The c.1136C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 379 (p.(Pro379Thr)) of NM_000545.6. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003898, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in 13 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 (PMIDs 21170474, 15657605, internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a MODY probability calculator result >50% and negative genetic testing for HNF4A (PP4; internal lab contributor). This variant segregated with diabetes, with at least 4 informative meioses in 3 families (PP1_Strong; internal lab contributors). Another missense variant, c.1136C>G p.Pro379Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Pro379Thr (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS1, PP3, PP4, PP1_Strong, PM5_Supporting. -

Type 1 diabetes mellitus 20

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 07, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.38

D

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;D;D;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

1.0

D

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Pathogenic

0.86

D

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.1

D

PrimateAI

Pathogenic

0.83

D

PROVEAN

Uncertain

-4.0

D;.;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Benign

0.072

T;T;T;T

Polyphen

1.0

.;.;.;D

Vest4

0.95

MutPred

0.93

Loss of catalytic residue at P378 (P = 0.0116);Loss of catalytic residue at P378 (P = 0.0116);Loss of catalytic residue at P378 (P = 0.0116);Loss of catalytic residue at P378 (P = 0.0116);

MVP

0.98

MPC

0.59

ClinPred

0.94

D

GERP RS

4.6

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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: rs754729248; hg19: chr12-121434371;