NM_000458.4(HNF1B):c.949G>T (p.Ala317Ser) AND Renal cysts and diabetes syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Jul 6, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000030535.2

Allele description [Variation Report for NM_000458.4(HNF1B):c.949G>T (p.Ala317Ser)]

NM_000458.4(HNF1B):c.949G>T (p.Ala317Ser)

Gene:
HNF1B:HNF1 homeobox B [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q12
Genomic location:
Preferred name:
NM_000458.4(HNF1B):c.949G>T (p.Ala317Ser)
HGVS:
  • NC_000017.11:g.37731691C>A
  • NG_013019.2:g.18416G>T
  • NM_000458.3(HNF1B):c.949G>T
  • NM_000458.4:c.949G>TMANE SELECT
  • NM_001165923.4:c.871G>T
  • NM_001304286.2:c.871G>T
  • NP_000449.1:p.Ala317Ser
  • NP_001159395.1:p.Ala291Ser
  • NP_001291215.1:p.Ala291Ser
  • NC_000017.10:g.36091682C>A
  • NM_000458.2:c.949G>T
  • NM_000458.3(HNF1B):c.949G>T
  • NM_000458.3:c.949G>T
Protein change:
A291S
Links:
Molecular consequence:
  • NM_000458.4:c.949G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001165923.4:c.871G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001304286.2:c.871G>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Renal cysts and diabetes syndrome (RCAD)
Synonyms:
Maturity-onset diabetes of the young, type 5; MODY type 5; Hyperuricemic nephropathy, familial juvenile, atypical; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007669; MedGen: C0431693; Orphanet: 93111; OMIM: 137920

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000053206Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
likely pathogenic
(Aug 18, 2011)
germlinecuration, clinical testing

Citation Link,

SCV000926043Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnbergcriteria provided, single submitter
Uncertain significance
(Jul 6, 2019)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV001423105Broad Institute Rare Disease Group, Broad Instituteno assertion criteria providedUncertain significance
(Jan 22, 2020)
germlinecuration

Citation Link

Description

This variant and it's classification has been reported by Vasileiou et al. 2019; DOI:10.1101/576918. The variants has previously been reported in ClinVar:36854 as "NM_000458.3(HNF1B):c.949G>T (p.Ala317Ser)" with clinical significance Likely pathogenic. It has been re-classified using InterVar and manual curation as Uncertain significance based on PM1 PP3 PP5.

SCV000926043

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedliterature only, curation
not providedgermlineunknown1not providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000053206.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided
2not providednot providednot providednot providedclinical testingnot provided

Description

Converted during submission to Likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providedBloodassert pathogenicitynot providednot providednot providednot provided
2germlineunknownnot providedBloodassert pathogenicitynot providednot providednot provided See 2

Co-occurrences

#ZygosityAllelesNumber of Observations
2SingleHeterozygoteHNF4A:c.416C>T, TCF1:c.864G>C, TCF1:c.79A>C, TCF1:c.51C>G, TCF1:c.1545G>A, TCF1:c.1501+7G>A, TCF1:c.1460G>A, TCF1:c.1375C>T, TCF1:c.1720A>G, TCF1:c.1137delT1

From Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, SCV000926043.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Broad Institute Rare Disease Group, Broad Institute, SCV001423105.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The p.Ala317Ser variant in HNF1B has been reported in at least 1 individual with Renal Cysts and Diabetes Syndrome in ClinVar (Variation ID: 36854), and has been identified in 0.008674% (3/34588) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922492). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36854). In summary, the clinical significance of the p.Ala317Ser variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3 (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Aug 27, 2021

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