Submissions for variant NM_000875.5(IGF1R):c.3348_3366dup (p.Met1123fs)

dbSNP: rs1322503729

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497309	SCV000589574	pathogenic	not provided	2021-11-29	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate nonsense-mediated mRNA decay and attenuated activation of the IGF1R pathway (Fang et al., 2009); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19240156, 26578640, 26252249, 25866162, 25040157, 22180424, 21396585, 21204214, 14657428, 28395282)
Ambry Genetics	RCV000624750	SCV000741523	pathogenic	Inborn genetic diseases	2020-02-25	criteria provided, single submitter	clinical testing	The alteration results in a premature stop codon: The c.3348_3366dup19 (p.M1123Rfs*14) alteration, located in coding exon 18 of the IGF1R gene, consists of a duplication of the 19 nucleotides at position 3348 to 3366, causing a translational frameshift with a predicted alternate stop codon after 14 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration has been observed in affected individuals: This alteration was identified in one family with short stature. The proband's height was -3.1 SDS, the mother's was -4.6 SDS, the sibling's was -1.94 SDS, and several other maternal family members were also reported to have short stature. Unlike other reported patients with IGF1R alterations, the proband was described to have normal circulating levels of GH binding protein, IGF-I, and IGF binding protein 2 (Fang, 2009). Functional analysis reveals a damaging effect of the amino acid alteration: Analyses of the primary dermal fibroblasts in a family with this alteration revealed a reduced amount of the normal IGF1R protein and diminished activation of the IGF1R pathway (Fang, 2009). Based on the available evidence, this alteration is classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000497309	SCV002051476	pathogenic	not provided	2020-11-16	criteria provided, single submitter	clinical testing	PVS1, PS3, PM2
Invitae	RCV000497309	SCV002240571	pathogenic	not provided	2021-05-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with autosomal dominant short stature (PMID: 19240156). ClinVar contains an entry for this variant (Variation ID: 431965). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met1123Argfs*14) in the IGF1R gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IGF1R are known to be pathogenic (PMID: 14657428).