VCV000068732.10 - ClinVar

NM_000207.3(INS):c.308A>G (p.Tyr103Cys)

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.

(4)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Likely risk allele(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000207.3(INS):c.308A>G (p.Tyr103Cys)

Variation ID: 68732 Accession: VCV000068732.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 2159877 (GRCh38) [ NCBI UCSC ] 11: 2181107 (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	Oct 31, 2013	Feb 14, 2024	Nov 6, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000207.3:c.308A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000198.1:p.Tyr103Cys	missense
NM_001042376.3:c.187+908A>G		intron variant
NM_001185097.2:c.308A>G	NP_001172026.1:p.Tyr103Cys	missense
NM_001185098.2:c.308A>G	NP_001172027.1:p.Tyr103Cys	missense
NM_001291897.2:c.308A>G	NP_001278826.1:p.Tyr103Cys	missense
NC_000011.10:g.2159877T>C
NC_000011.9:g.2181107T>C
NG_007114.1:g.6318A>G
NG_050578.1:g.6333A>G
	P01308:p.Tyr103Cys

... more HGVS ... less HGVS

Protein change

Y103C

Other names

Canonical SPDI

NC_000011.10:2159876:T:C

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.

Links

ClinGen: CA266175 UniProtKB: P01308#VAR_063740 UniProtKB/Swiss-Prot: VAR_063740 dbSNP: rs121908277 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.
INS		No evidence available	No evidence available	GRCh38 GRCh37	12	202
INS-IGF2	-	-	-	GRCh38 GRCh37	-	330

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.
Permanent neonatal diabetes mellitus	Likely pathogenic (2)	criteria provided, single submitter	Mar 28, 2017	RCV000059614.6
not provided	Uncertain significance (1)	criteria provided, single submitter	Nov 6, 2021	RCV001854250.5
Diabetes mellitus, permanent neonatal 4	Likely risk allele (1)	criteria provided, single submitter	-	RCV003389039.1

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.
Likely pathogenic (Mar 28, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Diabetes mellitus, permanent neonatal Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000595240.1 First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013
Likely risk allele (-)	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1) Method: research	Diabetes mellitus, permanent neonatal 4 Affected status: unknown Allele origin: unknown	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV004041825.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023	Publications: PubMed (4) PubMed: 18162506‚ 25542748‚ 20724178‚ 20938745 Comment: Potent mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. It may have poor response to sulfonylureas, as mutations in … (more) Potent mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. It may have poor response to sulfonylureas, as mutations in this gene can cause beta cell destruction. Sufficient evidence is found to confer the association of this particular variant rs121908277 with permanent neonatal diabetes mellitus. (less) Comment on evidence: rs1046314 variant is associated with the permanent neonatal diabetes
Uncertain significance (Nov 06, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002179255.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 18162506‚ 30191644 Comment: This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 103 of the INS protein … (more) This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 103 of the INS protein (p.Tyr103Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant permanent neonatal diabetes mellitus and/or INS-related conditions (PMID: 18162506, 30191644). ClinVar contains an entry for this variant (Variation ID: 68732). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
not provided (-)	no classification provided Method: not provided	Permanent neonatal diabetes mellitus Affected status: not provided Allele origin: not provided	UniProtKB/Swiss-Prot Accession: SCV000091163.1 First in ClinVar: Oct 31, 2013 Last updated: Oct 31, 2013

Comment:

Potent mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. It may have poor response to sulfonylureas, as mutations in this gene can cause beta cell destruction. Sufficient evidence is found to confer the association of this particular variant rs121908277 with permanent neonatal diabetes mellitus.

Comment:

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 103 of the INS protein (p.Tyr103Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant permanent neonatal diabetes mellitus and/or INS-related conditions (PMID: 18162506, 30191644). ClinVar contains an entry for this variant (Variation ID: 68732). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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
Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort.	Johnson SR	Pediatric diabetes	2019	PMID: 30191644
INS-gene mutations: from genetics and beta cell biology to clinical disease.	Liu M	Molecular aspects of medicine	2015	PMID: 25542748
Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene.	Støy J	Reviews in endocrine & metabolic disorders	2010	PMID: 20938745
Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth.	Liu M	Trends in endocrinology and metabolism: TEM	2010	PMID: 20724178
Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.	Edghill EL	Diabetes	2008	PMID: 18162506

Text-mined citations for rs121908277 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000207.3(INS):c.308A>G (p.Tyr103Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908277 ...