12-120994314-GC-GCC

Variant names:

• chr12-120994314-G-GC
• rs587776825
• NM_000545.8:c.872dupC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PP1_Strong PS2_Moderate

This summary comes from the ClinGen Evidence Repository: The c.872dupC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 292 (NM_000545.8), adding 25 novel amino acids before encountering a stop codon (p.(Gly292ArgfsTer25)). 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 100 informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual and unconfirmed parental relationships in another individual with diabetes, but whose clinical picture is suggestive but not highly specific for HNF1A-MODY (MODY probability calculator result >50% but HNF4A not tested) (PS2_Moderate; PMID:9166684, internal lab contributors). The variant is located in a poly-C tract and failed QC in gnomAD v2.1.1 in a manner typical of single base deletions in poly-C tracts in NGS; therefore, PM2_Supporting could not be applied. This variant was identified in at least 200 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because PM2_Supporting cannot be applied (internal lab contributors). In summary, c.872dupC 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 9/30/21): PVS1, PS2_Moderate, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA124453/MONDO:0015967/017

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: HNF1A NM_000545.8 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• 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 14 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.872dupC	p.Gly292ArgfsTer25	frameshift_variant	Exon 4 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.872dupC	p.Gly292ArgfsTer25	frameshift_variant	Exon 4 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.872dupC	p.Gly292ArgfsTer25	frameshift_variant	Exon 4 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.872dupC	p.Gly292ArgfsTer25	frameshift_variant	Exon 4 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.872dupC	p.Gly292ArgfsTer25	frameshift_variant	Exon 4 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151666 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000571 AC: 83 AN: 1452716 Hom.: 0 Cov.: 35 AF XY: 0.0000609 AC XY: 44 AN XY: 722230

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000929

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00105

Gnomad4 NFE exome AF: 0.0000163

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151666 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74028

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000442 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

Maturity onset diabetes mellitus in young Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2023	Variant summary: HNF1A c.872dupC (p.Gly292ArgfsX25) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00037 in 228182 control chromosomes (gnomAD), however the variant failed random forest filters and therefore the available allele frequency data may not be reliable. c.872dupC has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 3 (e.g., Vesterhus_2008, Yamagata_1996, Yamada_1997, Glucksmann_1997, Barrio_2002). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12050210, 9166684, 9313763, 8945470, 17989309). Eight submitters, including the ClinGen Monogenic Diabetes Variant Curation Expert Panel, have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	research	Clinical 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. Sufficient evidence is found to confer the association of this particular variant rs587776825 with MODY3. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 04, 2023	The p.Gly292ArgfsX25 variant in HNF1A is the most frequently reported HNF1A variant and has been reported (initially as p.P291fsinsC) in more than 100 individuals with maturity-onset diabetes of the young (MODY; Colclough 2013 PMID: 23348805) and segregated with disease in at least 100 affected family members. It was also classified as pathogenic on April 23, 2022 by the ClinGen-approved Monogenic Diabetes expert panel (Variation ID 14927). Data from large population studies is insufficient to assess the frequency of this variant. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 292 and leads to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in autosomal dominant monogenic diabetes. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Strong. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 08, 2020	The c.872dupC pathogenic mutation, located in coding exon 4 of the HNF1A gene, results from a duplication of C at nucleotide position 872, causing a translational frameshift with a predicted alternate stop codon (p.G292Rfs*25). This mutation (designated as P291fsinsC) was first reported in a MODY family in which the mutation co-segregated with disease (Yamagata K et al. Nature, 1996 Dec;384:455-8). This is the most common HNF1A mutation; it has been reported in multiple maturity-onset diabetes of the young (MODY) families, as well as a de novo occurrence, and as a possible founder mutation in the Norwegian population (Colclough K et al. Hum. Mutat., 2013 May;34:669-85). An in vitro study quantified ectopically expressed mutant transcripts in lymphoblastoid cell lines and reduced mRNA levels to 6% of wild-type (Harries LW et al. Diabetes, 2004 Feb;53:500-4). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2022	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: 25174781, 21628466, 23551881, 29417725, 28170077, 12530534, 23607861, 8945470, 21051477, 27153395, 28012402, 29666556, 27913849, 29493090, 29927023, 28862987, 30814848, 30641602, 11058894, 12574234, 31291970, 32041611, 33031055) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 07, 2024	This sequence change creates a premature translational stop signal (p.Gly292Argfs*25) 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 autosomal dominant maturity-onset diabetes of the young 3 (MODY3) (PMID: 8945470, 28862987). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this HNF1A variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 34,079 individuals referred to our laboratory for HNF1A testing. This variant is also known as P291fsinsC. ClinVar contains an entry for this variant (Variation ID: 14927). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2023	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12530534) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 14, 2024	The HNF1A c.872dup; p.Gly292ArgfsTer25variant (rs587776825) is reported in the literature as a recurrent pathogenic variant found in multiple individuals and families affected maturity-onset diabetes of the young (Ellard 2000, Estalella 2007, Johnson 2018, Pavic 2018, Yamagata 1996). This variant is reported in ClinVar (Variation ID: 14927) and is found in the general population with an overall allele frequency of 0.03% (86/259326) in the Genome Aggregation Database. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Ellard S. Hepatocyte nuclear factor 1 alpha (HNF-1 alpha) mutations in maturity-onset diabetes of the young. Hum Mutat. 2000 Nov;16(5):377-85. PMID: 11058894. Estalella I et al. Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain. Clin Endocrinol (Oxf). 2007 Oct;67(4):538-46. PMID: 17573900. Johnson SR et al. Whole-exome sequencing for mutation detection in pediatric disorders of insulin secretion: Maturity onset diabetes of the young and congenital hyperinsulinism. Pediatr Diabetes. 2018 Jun;19(4):656-662. PMID: 29417725. Pavic T et al. Maturity onset diabetes of the young due to HNF1A variants in Croatia. Biochem Med (Zagreb). 2018 Jun 15;28(2):020703. PMID: 29666556. Yamagata K et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature. 1996 Dec 5;384(6608):455-8. PMID: 8945470. -

Maturity-onset diabetes of the young type 3 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2005	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Gly292Argfs25 variant in HNF1A has been reported in 7 individuals with maturity-onset diabetes of the young, segregated with disease in 6 affected relatives from 3 families (PMID: 25174781, 17573900) and has also been reported pathogenic by 4 unique submitters in ClinVar (Variation ID: 14927). Data from large population studies is insufficient to assess the frequency of this variant. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 292 and leads to a premature termination codon 25 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in maturity-onset diabetes of the young. 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 the predicted impact of the variant and segregation with disease in multiple families. ACMG/AMP Criteria applied: PVS1, PP1_Moderate, PS4_Supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	-	The p.Gly292Argfs*25 is predicted to substitute the glycine at amino acid position 292 with arginine, followed by a frameshift that results in a premature termination codon after 25 amino acids. The p.Gly292Argfs*25 variant has been observed in 20%-50% of individuals with HNF1A-related MODY (PMID: 8945470, 29417725, 35235779). Individuals with the p.Gly292Argfs*25 variant often show symptoms similar to those of type 1 diabetes (PMID: 29107759). Functional studies have shown defects in ß cell differentiation, consistent with pancreatic abnormalities observed in individuals with the p.Gly292Argfs*25 variant (PMID: 35235779). -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Maturity-onset diabetes of the young type III (MODY type III; MIM#600496). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple families with MODY (ClinVar, PMID: 34373539, PMID: 25555642). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Clear cell carcinoma of kidney Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2005

- -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 15, 2022

The c.872dupC variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 292 (NM_000545.8), adding 25 novel amino acids before encountering a stop codon (p.(Gly292ArgfsTer25)). 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 100 informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in one individual and unconfirmed parental relationships in another individual with diabetes, but whose clinical picture is suggestive but not highly specific for HNF1A-MODY (MODY probability calculator result >50% but HNF4A not tested) (PS2_Moderate; PMID:9166684, internal lab contributors). The variant is located in a poly-C tract and failed QC in gnomAD v2.1.1 in a manner typical of single base deletions in poly-C tracts in NGS; therefore, PM2_Supporting could not be applied. This variant was identified in at least 200 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because PM2_Supporting cannot be applied (internal lab contributors). In summary, c.872dupC 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 9/30/21): PVS1, PS2_Moderate, PP1_Strong. -

DiGeorge syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

-

- -

Hepatic adenomas, familial Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2005

- -

Diabetes mellitus type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 11, 2022

DNA sequence analysis of the HNF1A gene demonstrated a single base pair duplication in exon 4, c.872dup. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 24 amino acids downstream of the mutation, p.Gly292Argfs*25. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated HNF1A protein with potentially abnormal function. This pathogenic sequence change has previously been described in multiple patients and families with HNF1A-related MODY (PMIDs: 8945470, 27913849, PMID: 29666556). -

Type 1 diabetes mellitus 20 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2005

- -

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;