Submissions for variant NM_000381.4(MID1):c.388G>A (p.Ala130Thr)

dbSNP: rs1934582371

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001249712	SCV001423736	likely pathogenic	X-linked Opitz G/BBB syndrome	2019-12-05	criteria provided, single submitter	clinical testing	The MID1 c.388G>A (p.Ala130Thr) variant is a missense variant. Across a selection of the available literature, the p.Ala130Thr variant has been identified in at least two individuals in a hemizygous state, one of whom presented with laryngo-tracheo-esophageal defects and hypospadias and the other one presented with hypertelorism, broad nasal bridge, strabismus, cleft lip and palate, hypospadias and small ears with a right pre-auricular pit (Aranda-Orgillés et al. 2008; Fontanella et al. 2008). The p.Ala130Thr is not reported in the Genome Aggregation Database despite good sequence coverage, so the variant is presumed to be rare. The Ala130 residue is highly conserved and lies in the Bbox1 domain of the MID1 protein (Du et al. 2014). NMR studies and computational modeling revealed that the p.Ala130Thr variant Bbox1 domain failed to coordinate the structurally essential zinc ions and resulted in an unfolded structure (Zhao et al. 2015). In addition, the p.Ala130Thr variant protein was unable to catalyze the polyubiquitination of its substrate and while it bound to microtubules, it could not be actively transported (Aranda-Orgillés et al. 2008; Du et al. 2014). Another missense change at the same residue, p.Ala130Val has also been observed in an affected individual who had hypertelorism, cleft lip and palate, and laryngo-tracheo-esophageal defects (Fontanella et al. 2008). Based on the collective evidence, and application of the ACMG criteria, the p.Ala130Thr variant is classified as likely pathogenic for Opitz G/BBB syndrome.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002568698	SCV003444422	pathogenic	not provided	2024-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 130 of the MID1 protein (p.Ala130Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Opitz GBBB syndrome (PMID: 17221865, 18949047, 27749392; Invitae). ClinVar contains an entry for this variant (Variation ID: 973281). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MID1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MID1 function (PMID: 25207814). This variant disrupts the p.Ala130 amino acid residue in MID1. Other variant(s) that disrupt this residue have been observed in individuals with MID1-related conditions (PMID: 17221865, 27749392), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001249712	SCV005077498	pathogenic	X-linked Opitz G/BBB syndrome	2024-04-04	criteria provided, single submitter	clinical testing	Variant summary: MID1 c.388G>A (p.Ala130Thr) results in a non-conservative amino acid change located in the B-box-type zinc finger domain (IPR000315) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183398 control chromosomes (gnomAD). c.388G>A has been reported in the literature in male individuals affected with Opitz G/BBB syndrome, including at least two cases where it was reported as de novo (e.g. Ferrentino_2007, Aranda-Orgills_2008, Pinto_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant did not impair binding to microtubules, it severely reduced transport bidirectionally along microtubules (Aranda-Orgills_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18949047, 17221865, 27749392). ClinVar contains an entry for this variant (Variation ID: 973281). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001249712	SCV005679728	pathogenic	X-linked Opitz G/BBB syndrome	2024-04-05	criteria provided, single submitter	clinical testing