ClinVar Miner

Submissions for variant NM_001080483.3(MYMK):c.271C>A (p.Pro91Thr) (rs137868995)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group, Broad Institute RCV000495954 SCV001164470 likely pathogenic Congenital nonprogressive myopathy with Moebius and Robin sequences 2018-12-03 criteria provided, single submitter research The heterozygous p.Pro91Thr variant in TMEM8C was identified by our study in the compound heterozygous state, with a VUS, in one individual with Carey-Finteman-Ziter syndrome. This variant has been identified in 0.1186% (328/276516) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137868995). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Pro91Thr variant in MYMK has been reported in 7 Caucasian individuals from the US and New Zealand with Carey Finteman-Ziter syndrome and segregated with disease in 6 affected relatives from 3 families (PMID: 28681861). The presence of this variant in combination with 3 variants reported pathogenic by OMIM in ClinVar and in 7 individuals with Carey-Finteman-Ziter syndrome increases the likelihood that the p.Pro91Thr variant is pathogenic. In vitro functional studies provide some evidence that the p.Pro91Thr variant may impact, but not eliminate, myoblast fusion activity (PMID: 28681861). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PP1, PS3_Supporting (Richards 2015).
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV000495954 SCV001244964 pathogenic Congenital nonprogressive myopathy with Moebius and Robin sequences 2018-03-11 criteria provided, single submitter clinical testing A heterozygous missense variant NM_001080483.2(MYMK):c.271C>A, has been identified in exon 3 of 5 of the MYMK (TMEM8C) gene. The variant is predicted to result in a minor amino acid change from proline to threonine at position 91 of the protein (NP_001073952.1(MYMK):p.(Pro91Thr)). The proline residue at this position has very high conservation (100 vertebrates, UCSC), but is not located within a well established functional domain. In-silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.118% (328 het, 0 hom). The variant has previously reported in compound heterozygous state in 7 patients in 4 unrelated families (Di Gioia S.A. et al 2017). Functional assessment of the variant indicates that it does not result in a full null allele, although it does appear to diminish function of the protein (Di Gioia S.A. et al 2017). Analysis of parental samples indicated this variant was paternally inherited. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Illumina Clinical Services Laboratory,Illumina RCV000495954 SCV001451455 pathogenic Congenital nonprogressive myopathy with Moebius and Robin sequences 2019-06-05 criteria provided, single submitter clinical testing The MYMK c.271C>A (p.Pro91Thr) variant is a missense variant that has been reported in three studies and is found in a total of 11 individuals from six families with phenotypes overlapping Carey-Fineman-Ziter syndrome, all carrying the variant in a compound heterozygous state with a second missense variant (Di Gioia et al. 2017; Alrohaif et al. 2018; Hedberg-Oldfors et al. 2018). Individuals ranged in age from one to 69 years and the main phenotypes included facial muscle weakness, motor delays, generalized muscle hypoplasia, congenital contractures, hypermobility, myopathy noted through electromyography, growth failure, feeding problems, skeletal features including scoliosis and short stature, and facial and head features including broad nasal tip, micrognathia or retrognathia, lagophthalmos, ptosis, high palate, cleft palate, and a thin tubular neck. Parents were also genotyped in five of the families, showing an unaffected parent carrying the variant in a heterozygous state (Di Gioia et al. 2017; Hedberg-Oldfors et al. 2018). Control data are unavailable for this variant, which is reported at a frequency of 0.002192 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies showed an effect on protein stability in HeLa cells and lower expression levels in C2C12 cells with FLAG-tagged human p.Pro91Thr constructs. However, presence of this variant did not affect myoblast fusion. In zebrafish studies, the p.Pro91Thr variant partially rescued the phenotype, whereas there was complete rescue with wild-type mRNA (Di Gioia et al. 2017). Based on the collective evidence, the p.Pro91Thr variant is classified as pathogenic for Carey-Fineman-Ziter syndrome.
Baylor Genetics RCV000495954 SCV001525178 uncertain significance Congenital nonprogressive myopathy with Moebius and Robin sequences 2019-07-18 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM RCV000495954 SCV000583972 pathogenic Congenital nonprogressive myopathy with Moebius and Robin sequences 2019-01-07 no assertion criteria provided literature only
GeneDx RCV001575718 SCV001802767 uncertain significance not provided 2020-10-31 no assertion criteria provided clinical testing In silico analysis supports that this missense variant does not alter protein structure/function, and published functional studies suggest residual protein activity is more similar to wild type activity than to null allele activity (Di Gioia et al., 2017); This variant is associated with the following publications: (PMID: 32528171, 28681861, 32333597, 32573669, 29560417, 30065953, 7131178)

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