chr12-120994314-G-GC
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PP1_StrongPS2_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
Consequence
NM_000545.8 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
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 0.00000659 AC: 1AN: 151666Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000571 AC: 83AN: 1452716Hom.: 0 Cov.: 35 AF XY: 0.0000609 AC XY: 44AN XY: 722230
GnomAD4 genome 0.00000659 AC: 1AN: 151666Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74028
ClinVar
Submissions by phenotype
Maturity onset diabetes mellitus in young Pathogenic:4
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. -
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. -
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. -
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. -
not provided Pathogenic:4
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) -
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) -
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. -
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. -
Maturity-onset diabetes of the young type 3 Pathogenic:4
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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). -
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 -
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). -
Clear cell carcinoma of kidney Pathogenic:1
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DiGeorge syndrome Pathogenic:1
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Monogenic diabetes Pathogenic:1
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. -
Hepatic adenomas, familial Pathogenic:1
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Diabetes mellitus type 1 Pathogenic:1
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at