chr11-2159919-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PM1PM5PP3_StrongPP5BS2_Supporting
The NM_000207.3(INS):c.266G>A(p.Arg89His) variant causes a missense change. The variant allele was found at a frequency of 0.00000748 in 1,603,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R89C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000207.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
INS | NM_000207.3 | c.266G>A | p.Arg89His | missense_variant | 3/3 | ENST00000381330.5 | |
INS-IGF2 | NR_003512.4 | n.246+866G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
INS | ENST00000381330.5 | c.266G>A | p.Arg89His | missense_variant | 3/3 | 1 | NM_000207.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000435 AC: 1AN: 229810Hom.: 0 AF XY: 0.00000805 AC XY: 1AN XY: 124174
GnomAD4 exome AF: 0.00000620 AC: 9AN: 1451498Hom.: 0 Cov.: 35 AF XY: 0.00000694 AC XY: 5AN XY: 720976
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74348
ClinVar
Submissions by phenotype
Hyperproinsulinemia Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 03, 2022 | Variant summary: INS c.266G>A (p.Arg89His) results in a non-conservative amino acid change located in the Insulin-like domain (IPR016179) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-06 in 229810 control chromosomes (gnomAD). p.Arg89His (also described in the literature as Arg65His) has been reported in multiple individuals/families affected with Hyperproinsulinemia (e.g. Shibasaki_1995, Barbetti_1990, Oohashi_1993, Roder_1996, Collinet_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed the variant protein was properly sorted to secretory granules and efficiently secreted (Park_2010). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic for Hyperproinsulinemia. - |
Uncertain significance, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, as potent mutations in this gene can cause beta cell destruction. However, more evidence is required to confer the association of this particular variant rs28933985 (Arg65His) with hyperproinsulinemia. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1998 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2020 | - - |
INS-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 14, 2022 | The INS c.266G>A variant is predicted to result in the amino acid substitution p.Arg89His. This variant, also known as p.Arg65His using legacy nomenclature, has been reported in multiple individuals with hyperproinsulinemia (Robbins DC et al 1984. PubMed ID: 6368587; Shibasaki et al 1985. PubMed ID: 4019786; Röder ME et al 1996. PubMed ID: 8636380; Collinet M et al 1998. PubMed ID: 9667398; Park et al. 2010. PubMed ID: 20034470). This variant is reported in 0.00097% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-2181149-C-T). Alternative variants at the same amino acid ( p.Arg89Cys, p.Arg89Pro, and p.Arg89Leu) have also been reported in association with hyperproinsulinemia and diabetes (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/). This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at