rs587776825

Positions:

• chr12-120994314-GC-G
• chr12-120994314-GC-GCC
• chr12-120994314-GC-GCCC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP1_Moderate PVS1 PP4

This summary comes from the ClinGen Evidence Repository: The c.872del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 291 (NM_000545.8), adding 51 novel amino acids before encountering a stop codon (p.(Pro291GlnfsTer51). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). Additionally, this variant segregated with diabetes, with at least 30 informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). Additionally, 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) (PP4; internal lab contributors). In summary, c.872del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PP1_Strong, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831848/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: HNF1A NM_000545.8 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 1.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.872del	p.Pro291GlnfsTer51	frameshift_variant	4/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.872del	p.Pro291GlnfsTer51	frameshift_variant	4/10		NP_001293108.2
HNF1A	NM_001406915.1	c.872del	p.Pro291GlnfsTer51	frameshift_variant	4/9		NP_001393844.1
HNF1A	XM_024449168.2	c.872del	p.Pro291GlnfsTer51	frameshift_variant	4/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.872del	p.Pro291GlnfsTer51	frameshift_variant	4/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000550 AC: 8 AN: 1453500 Hom.: 0 Cov.: 35 AF XY: 0.00000692 AC XY: 5 AN XY: 722614

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000232

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.00000542

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	This sequence change creates a premature translational stop signal (p.Pro291Glnfs*51) in the HNF1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1A are known to be pathogenic (PMID: 15928245, 18003757). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 9097962, 11719843). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 805637). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2021	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31447099, 31658956, 30476138, 30293189, 9097962, 26287533, 25414397, 25555642, 30455330, 22432108, 29493090, 11719843, 23348805) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 06, 2020	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 10, 2022	The HNF1A c.872delC; p.Pro291GlnfsTer51 variant (rs587776825), also published as c.865delC, is reported in the literature in several individuals with monogenic diabetes and segregates with disease in at least one large family (Benonisdottir 2019, Kristinsson 2001, Li 2020, Sturiale 2021, Tung 2018). The variant is reported as pathogenic by an FDA-recognized expert panel (ClinVar Variation ID: 805637) and is listed in the general population with an overall allele frequency of 0.006% (14/228,182 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (Colclough 2013). Based on available information, this variant is classified as pathogenic. References: Literature cited: Benonisdottir S et al. Sequence variants associating with urinary biomarkers. Hum Mol Genet. 2019 Apr 1;28(7):1199-1211. PMID: 30476138. Colclough K et al. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat. 2013 May;34(5):669-85. PMID: 23348805. Kristinsson SY et al. MODY in Iceland is associated with mutations in HNF-1alpha and a novel mutation in NeuroD1. Diabetologia. 2001 Nov;44(11):2098-103. PMID: 11719843. Li M et al. High Prevalence of a Monogenic Cause in Han Chinese Diagnosed With Type 1 Diabetes, Partly Driven by Nonsyndromic Recessive WFS1 Mutations. Diabetes. 2020 Jan;69(1):121-126. PMID: 31658956. Sturiale L et al. Aberrant sialylation in a patient with a HNF1alpha variant and liver adenomatosis. iScience. 2021 Mar 18;24(4):102323. PMID: 33889819. Tung JY et al. Clinical heterogeneity of hyperinsulinism due to HNF1A and HNF4A mutations. Pediatr Diabetes. 2018 Aug;19(5):910-916. PMID: 29493090. -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Dec 31, 2021

The c.872del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 291 (NM_000545.8), adding 51 novel amino acids before encountering a stop codon (p.(Pro291GlnfsTer51). This variant, located in biologically-relevant exon 4 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID:23348805). Additionally, this variant segregated with diabetes, with at least 30 informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). Additionally, 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) (PP4; internal lab contributors). In summary, c.872del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 6/4/2021): PVS1, PP1_Strong, PP4 -

Maturity-onset diabetes of the young type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

research

deCODE genetics, Amgen

Jul 21, 2023

The variant NM_000545.8:c.872del (chr12:120994314) in HNF1A was detected in 10 heterozygotes out of 58K WGS Icelanders (MAF= 0,009%). Following imputation in a set of 166K Icelanders (55 imputed heterozygotes) we observed an association with diabetes mellitus using 3676 cases and 332804 controls (OR= 44.86, P= 9.00e-17), non-insulin dependent diabetes mellitus using 5864 cases and 298172 controls (OR= 35.60, P= 6.24e-15), and Type 1 diabetes using 2460 cases and 338479 controls (OR= 19.45, P= 4.46e-09). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs587776825; hg19: chr12-121432117;