VCV000014934.3 - ClinVar

NM_000545.8(HNF1A):c.955G>A (p.Gly319Ser)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000545.8(HNF1A):c.955G>A (p.Gly319Ser)

Variation ID: 14934 Accession: VCV000014934.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q24.31 12: 120994405 (GRCh38) [ NCBI UCSC ] 12: 121432208 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 22, 2016	Jun 3, 2023	Apr 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000545.8:c.955G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000536.6:p.Gly319Ser	missense
NM_000545.6:c.955G>A
NM_001306179.2:c.955G>A	NP_001293108.2:p.Gly319Ser	missense
NC_000012.12:g.120994405G>A
NC_000012.11:g.121432208G>A
NG_011731.2:g.20660G>A
LRG_522:g.20660G>A

... more HGVS ... less HGVS

Protein change

G319S

Other names

Canonical SPDI

NC_000012.12:120994404:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA124463 OMIM: 142410.0008 dbSNP: rs137853240 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
HNF1A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	911	1002

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Diabetes mellitus type 2, susceptibility to	risk factor (1)	no assertion criteria provided	Apr 2, 2002	RCV000016071.4
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 12, 2023	RCV003230366.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Apr 12, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003929059.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (9) PubMed: 10084598‚ 16241915‚ 17116178‚ 17425917‚ 16186275‚ 11904371‚ 32041611‚ 18586913‚ 35299962 Comment: Variant summary: HNF1A c.955G>A (p.Gly319Ser) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of … (more) Variant summary: HNF1A c.955G>A (p.Gly319Ser) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant, located in the exonic-splice region alters the conserved last nucleotide of exon 4 adjacent to the canonical intronic splice donor site. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' splice donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Triggs-Raine_2002). Two abnormal transcripts present only in the G319S cell line included premature termination codons as a result of the inclusion of seven nucleotides from intron 4 or the deletion of exon 8. The variant allele was found at a frequency of 0.00028 in 206130 control chromosomes, predominantly at a frequency of 0.087 among the Ontario Oji-Cree nondiabetic control chromosomes (Hegele_1999). The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), strongly suggesting that the variant is benign. c.955G>A has been reported in the literature as a risk factor associated with a risk for Type 2 diabetes characterized by onset at an earlier age, higher postprandial plasma glucose, and lower body mass index (BMI) (Hegele_1999). These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. At least one publication reports experimental evidence evaluating an impact on protein function (Triggs-Raine_2002). The most pronounced variant effect results in an approximately 50% reduction in transcription ability while not affecting DNA binding or protein stability in-vitro. The combination of the reduced activity of the G319S protein and abnormal splicing transcripts has been thought to increase the susceptibility to diabetes (Li_2022). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the conflicting evidence outlined above, the variant was classified as uncertain significance in association to Maturity Onset Diabetes Of The Young 3. (less)
risk factor (Apr 02, 2002)	no assertion criteria provided Method: literature only	TYPE 2 DIABETES MELLITUS, SUSCEPTIBILITY TO Affected status: not provided Allele origin: germline	OMIM Accession: SCV000036339.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 08, 2020	Publications: PubMed (3) PubMed: 10084598‚ 10843190‚ 11904371 Comment on evidence: Hegele et al. (1999) identified a gly319-to-ser (G319S) variant in the HNF1A gene in Ontario Oji-Cree with early-onset type 2 diabetes (125853). G319S is in … (more) Hegele et al. (1999) identified a gly319-to-ser (G319S) variant in the HNF1A gene in Ontario Oji-Cree with early-onset type 2 diabetes (125853). G319S is in the proline II-rich domain of the trans-activation site of HNF1A and alters a glycine residue that is conserved throughout evolution. S319 was absent from 990 alleles from 6 other ethnic groups, suggesting that it is private for Oji-Cree. The S319 allele was more prevalent in diabetic than in nondiabetic Oji-Cree (0.209 vs 0.087; P = 0.000001). S319/S319 homozygotes and S319/G319 heterozygotes, respectively, had odds ratios for type 2 diabetes of 4.00 (95% CI, 2.65-6.03) and 1.97 (95% CI, 1.44-2.70) compared with G319/G319 homozygotes. There was a significant difference in the mean age of onset of type 2 diabetes, with G319/G319, S319/G319, and S319/S319 subjects being affected in the fifth, fourth, and third decades of life, respectively. Among nondiabetic subjects, S319/G319 heterozygotes had significantly lower plasma insulin than G319/G319 homozygotes. The authors concluded that the G319S variant is associated with a distinct form of type 2 diabetes, characterized by onset at an earlier age, lower body mass, and a higher postchallenge plasma glucose. That the majority of Oji-Cree subjects with diabetes did not have the HNF1A S319 variant suggested to Hegele et al. (2000) that there might be other genetic determinants of diabetes susceptibility. In the course of sequencing candidate genes in diabetic subjects who were homozygous for HNF1A G319/G319, they found that some subjects had the PPARG A12 variant (601487.0002). PPARG A12 was strongly associated with type 2 diabetes in women, but not in men. The authors concluded that, when taken together with the previously reported association of diabetes with HNF1A in both men and women, the gender-specific association with PPARG A12 confirms that type 2 diabetes is etiologically complex in the Oji-Cree and that at least 2 genes are involved in determining susceptibility to the disease in this population. Triggs-Raine et al. (2002) stated that Oji-Cree type 2 diabetes does not resemble MODY, because affected Oji-Cree subjects are obese and insulin-resistant with elevated plasma insulin concentrations, which clearly were insufficient to prevent diabetes onset. They evaluated the in vitro function of HNF1A G319S both to confirm that the mutation had a functional effect and to determine whether this effect was distinct from those of the complete loss-of-function or dominant-negative mutations seen in the MODY3 phenotype. They also evaluated the impact of the HNF1A G319S mutation on the dynamics of type 2 diabetes onset in the whole Sandy Lake Oji-Cree community. They found that the G319S mutation reduced the in vitro ability of HNF1-alpha to activate transcription by approximately 50%, with no effect on DNA binding or protein stability. There was no evidence of a dominant-negative effect of the mutant protein. Disease onset showed significant differences according to G319S genotype when gauged by the age at which half the subjects had become diabetic. Each dose of G319S accelerated median disease onset by approximately 7 years. Thus, the transactivation-deficient HNF1A G319S mutation affects the dynamics of disease onset. The demonstration of a functional consequence for the G319S mutation provided a mechanistic basis for its strong association with Oji-Cree type 2 diabetes and its unparalleled specificity for diabetes prediction in these people, in whom diabetes presents a significant public health problem. The finding also showed that HNF1A mutations can be associated with typical adult-onset insulin-resistant obesity-related diabetes in addition to maturity-onset diabetes of the young. Triggs-Raine et al. (2002) stated that in the Oji-Cree, HNF1A G319S behaves as a susceptibility allele for type 2 diabetes. Among nondiabetic Oji-Cree, fasting plasma insulin concentration was reduced significantly in HNF1A G319S carriers, suggesting that the partial impairment of function is tolerated when there is no insulin resistance. However, among Oji-Cree with type 2 diabetes, both carriers and noncarriers of the mutation had elevated plasma insulin concentration compared with nondiabetic Oji-Cree. The stress of obesity-induced insulin resistance seemed to expose the partial defect in HNF1A G319S carriers, causing expression of the disease. (less)

Comment:

Variant summary: HNF1A c.955G>A (p.Gly319Ser) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant, located in the exonic-splice region alters the conserved last nucleotide of exon 4 adjacent to the canonical intronic splice donor site. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens the canonical 5' splice donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Triggs-Raine_2002). Two abnormal transcripts present only in the G319S cell line included premature termination codons as a result of the inclusion of seven nucleotides from intron 4 or the deletion of exon 8. The variant allele was found at a frequency of 0.00028 in 206130 control chromosomes, predominantly at a frequency of 0.087 among the Ontario Oji-Cree nondiabetic control chromosomes (Hegele_1999). The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05), strongly suggesting that the variant is benign. c.955G>A has been reported in the literature as a risk factor associated with a risk for Type 2 diabetes characterized by onset at an earlier age, higher postprandial plasma glucose, and lower body mass index (BMI) (Hegele_1999). These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. At least one publication reports experimental evidence evaluating an impact on protein function (Triggs-Raine_2002). The most pronounced variant effect results in an approximately 50% reduction in transcription ability while not affecting DNA binding or protein stability in-vitro. The combination of the reduced activity of the G319S protein and abnormal splicing transcripts has been thought to increase the susceptibility to diabetes (Li_2022). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the conflicting evidence outlined above, the variant was classified as uncertain significance in association to Maturity Onset Diabetes Of The Young 3.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus.	Li LM	Frontiers in endocrinology	2022	PMID: 35299962
Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias.	Dron JS	BMC medical genomics	2020	PMID: 32041611
Diabetes susceptibility in the Canadian Oji-Cree population is moderated by abnormal mRNA processing of HNF1A G319S transcripts.	Harries LW	Diabetes	2008	PMID: 18586913
Insights on pathogenesis of type 2 diabetes from MODY genetics.	Weedon MN	Current diabetes reports	2007	PMID: 17425917
HNF-1alpha G574S is a functional variant with decreased transactivation activity.	Navalón-García K	Diabetic medicine : a journal of the British Diabetic Association	2006	PMID: 17116178
Synergism between mutant HNF1A and the metabolic syndrome in Oji-Cree Type 2 diabetes.	Pollex RL	Diabetic medicine : a journal of the British Diabetic Association	2005	PMID: 16241915
A prevalent amino acid polymorphism at codon 98 (Ala98Val) of the hepatocyte nuclear factor-1alpha is associated with maturity-onset diabetes of the young and younger age at onset of type 2 diabetes in Asian Indians.	Anuradha S	Diabetes care	2005	PMID: 16186275
HNF-1alpha G319S, a transactivation-deficient mutant, is associated with altered dynamics of diabetes onset in an Oji-Cree community.	Triggs-Raine BL	Proceedings of the National Academy of Sciences of the United States of America	2002	PMID: 11904371
Peroxisome proliferator-activated receptor-gamma2 P12A and type 2 diabetes in Canadian Oji-Cree.	Hegele RA	The Journal of clinical endocrinology and metabolism	2000	PMID: 10843190
The hepatic nuclear factor-1alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree.	Hegele RA	The Journal of clinical endocrinology and metabolism	1999	PMID: 10084598

Text-mined citations for rs137853240 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 26, 2024

ClinVar Genomic variation as it relates to human health

NM_000545.8(HNF1A):c.955G>A (p.Gly319Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137853240 ...