rs121908261

chr11-2160809-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Moderate PP5_Strong

The NM_000207.3(INS):c.163C>T(p.Arg55Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as other (★★).

• Frequency: Genomes: not found (cov: 35)
• Consequence: INS NM_000207.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic/Likely risk allele criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 3.08

Genes affected

INS (HGNC:6081): (insulin) This gene encodes insulin, a peptide hormone that plays a vital role in the regulation of carbohydrate and lipid metabolism. After removal of the precursor signal peptide, proinsulin is post-translationally cleaved into three peptides: the B chain and A chain peptides, which are covalently linked via two disulfide bonds to form insulin, and C-peptide. Binding of insulin to the insulin receptor (INSR) stimulates glucose uptake. A multitude of mutant alleles with phenotypic effects have been identified, including insulin-dependent diabetes mellitus, permanent neonatal diabetes diabetes mellitus, maturity-onset diabetes of the young type 10 and hyperproinsulinemia. There is a read-through gene, INS-IGF2, which overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region. [provided by RefSeq, May 2020]

INS-IGF2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000207.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926
• PP5: Variant 11-2160809-G-A is Pathogenic according to our data. Variant chr11-2160809-G-A is described in ClinVar as [other]. Clinvar id is 13392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_risk_allele=1, Likely_pathogenic=2, Pathogenic=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS	NM_000207.3	c.163C>T	p.Arg55Cys	missense_variant	2/3	ENST00000381330.5
INS-IGF2	NR_003512.4	n.222C>T		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000381330.5	c.163C>T	p.Arg55Cys	missense_variant	2/3	1	NM_000207.3	P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 88

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic/Likely pathogenic/Likely risk allele

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2021	Published functional studies demonstrate that R55C leads to the reduction of proinsulin secretion from the ER and potential activation of the ER stress response (Meur et al., 2010; Liu et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23624530, 20938745, 20007936, 20948967, 27913849, 25721872, 20226046, 18192540) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 30, 2019	DNA sequence analysis of the INS gene demonstrated a sequence change, c.163C>T, in exon 2 that results in an amino acid change, p.Arg55Cys. The p.Arg55Cys change affects a moderately conserved amino acid residue located in a domain of the INS protein that is known to be functional. The p.Arg55Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Arg55Cys change has been reported in a mother and daughter with type 1 diabetes with onset at 13 and 10 years of age; the p.Arg55Cys change was found to be a de novo change in the mother (PMID: 18192540). This sequence change has been described in the gnomAD database with a very low population frequency of 0.0004% (dbSNP rs121908261). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 10, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects INS function (PMID: 20007936, 20948967). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 13392). This missense change has been observed in individual(s) with autosomal dominant INS-related conditions (PMID: 18192540, 20007936; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121908261, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 55 of the INS protein (p.Arg55Cys). -

Type 1 diabetes mellitus 2 Pathogenic:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2008	- -

Monogenic diabetes Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 19, 2024

Variant summary: INS c.163C>T (p.Arg55Cys) 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 frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.163C>T has been reported in the literature in multiple individuals affected with Monogenic Diabetes (example: Molven_2008, Meur_2010, Petruzelkova_2016, Colclough_2022). The variant segregated with the disease in two independent families (Molven_2008, and Meur_2010) and at-least one case is reported as a de novo occurrence (Molven_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that R55C leads to the reduction of proinsulin secretion from the ER (Meur_2010). The following publications have been ascertained in the context of this evaluation (PMID: 26641800, 34789499, 20007936, 18192540). ClinVar contains an entry for this variant (Variation ID: 13392). Based on the evidence outlined above, the variant was classified as pathogenic. -

Diabetes mellitus type 1 Pathogenic:1

Likely risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in the INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, mutations in this gene can cause beta cell destruction. Sufficient evidence is found to confer the association of this particular variant rs121908261 with type1B Diabetes mellitus. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;D;D;D;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	D;.;.;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	0.69	N;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PROVEAN	Uncertain	-4.0	D;D;D;D;D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.;D
Polyphen		1.0	D;D;D;D;.;D
Vest4		0.47
MutPred		0.71		Loss of disorder (P = 0.0143);Loss of disorder (P = 0.0143);Loss of disorder (P = 0.0143);Loss of disorder (P = 0.0143);Loss of disorder (P = 0.0143);Loss of disorder (P = 0.0143);
MVP		0.91
MPC		1.0
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.97
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908261; hg19: chr11-2182039;