Submissions for variant NM_012064.4(MIP):c.638del (p.Gly213fs)

dbSNP: rs398122378

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043661	SCV000654109	pathogenic	Cataract 15 multiple types	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly213Valfs*46) in the MIP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acid(s) of the MIP protein. This variant is present in population databases (rs398122378, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with congenital cataracts (PMID: 16564824; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as Nt 3223del G. ClinVar contains an entry for this variant (Variation ID: 50960). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects MIP function (PMID: 18501347). For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000043661	SCV002061515	pathogenic	Cataract 15 multiple types	2021-08-23	criteria provided, single submitter	clinical testing	PVS1, PS3, PM2
GeneDx	RCV002281048	SCV002569697	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 51 amino acids are replaced with 45 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies are discrepant regarding the effect of the variant on protein localization and function (Varadaraj et al., 2008; Xiu et al., 2019); This variant is associated with the following publications: (PMID: 16564824, 18501347, 30585525, 10937580)
Ambry Genetics	RCV004018927	SCV004907400	likely pathogenic	Inborn genetic diseases	2023-10-13	criteria provided, single submitter	clinical testing	The c.638delG (p.G213Vfs*46) alteration, located in exon 4 (coding exon 4) of the MIP gene, consists of a deletion of one nucleotide at position 638, causing a translational frameshift with a predicted alternate stop codon after 46 amino acids. This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of MIP has not been established as a mechanism of disease. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/249660) total alleles studied. The highest observed frequency was 0.001% (1/111956) of European (non-Finnish) alleles. This variant has been found to segregate with disease in multiple family members affected with congenital cataracts (Geyer, 2006). Functional studies demonstrated that this variant is non-functional due to its failure to properly traffic to the plasma membrane and induce cell death by necrosis through the loss of cell membrane integrity (Varadaraj, 2008). In another study, this variant did not significantly alter the localization and reduce cell proliferation compared to the wildtype MIP protein (Xiu, 2019). Based on the available evidence, this alteration is classified as likely pathogenic.
OMIM	RCV000043661	SCV000071683	pathogenic	Cataract 15 multiple types	2006-04-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003407418	SCV004113923	pathogenic	MIP-related disorder	2024-04-17	no assertion criteria provided	clinical testing	The MIP c.638delG variant is predicted to result in a frameshift and premature protein termination (p.Gly213Valfs*46). This variant has been reported as segregating with disease in a large kindred with autosomal dominant cataracts (referred to as nt 3223 in Geyer et al. 2006. PubMed ID: 16564824). Functional studies using protein expression in xenopus oocytes showed that this variant leads to protein retention in the endoplasmic reticulum (ER), preventing trafficking to the plasma membrane and decreasing cell membrane water permeability (Varadaraj et al. 2008. PubMed ID: 18501347). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in MIP are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/50960). Given the evidence, we interpret c.638del (p.Gly213Valfs*46) as pathogenic.