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

gnomAD frequency: 0.00125  dbSNP: rs137868995

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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	RCV003147484	SCV001244964	pathogenic	Carey-Fineman-Ziter syndrome 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Carey-Fineman-Ziter syndrome (MIM#254940). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (341 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously reported in many individuals with Carey-Fineman-Ziter syndrome (MIM#254940) (ClinVar, PMID: 28681861, 29560417). (SP) 0901 - This variant has strong evidence for segregation with disease. The variant has been reported to segregate with disease in at least five families (PMID: 28681861, PMID: 30065953) (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The variant is considered to be hypomorphic as it results in a partial loss of function rather than a null allele (PMID: 28681861). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Illumina Laboratory Services, 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.
GeneDx	RCV001575718	SCV001802767	likely pathogenic	not provided	2024-11-13	criteria provided, single submitter	clinical testing	Published functional studies suggest residual protein activity is more similar to wild type activity than to null allele activity (PMID: 28681861); Considered a hypomorphic allele and associated with milder disease (PMID: 29560417, 28681861); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 7131178, 30065953, 29560417, 32573669, 32333597, 32528171, 28681861, 38790073)
Revvity Omics, Revvity	RCV003147484	SCV002017854	likely pathogenic	Carey-Fineman-Ziter syndrome 1	2022-06-30	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003147484	SCV002503610	pathogenic	Carey-Fineman-Ziter syndrome 1	2020-11-30	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace proline with threonine at codon 91 of the MYMK protein (p.(Pro91Thr)). The proline residue is invariant across species (100 vertebrates, UCSC), and is located in a domain of unknown function. There is a small physicochemical difference between proline and threonine. The variant is present in a large population cohort at a frequency of 0.1% (rs137868995, 341/282,106 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified with a second allele in at least six individuals with congenital nonprogressive myopathy with Moebius and Robin sequences, and segregates in affected siblings in multiple families (PMID: 28681861, 29560417, 30065953). The variant is a hypomorph, and the fusogenic activity of the mutant protein is fully/partially rescued in a zebrafish model (PMID: 28681861). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Strong, PS3_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000495954	SCV002819542	pathogenic	Congenital nonprogressive myopathy with Moebius and Robin sequences	2022-12-02	criteria provided, single submitter	clinical testing	Variant summary: MYMK c.271C>A (p.Pro91Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 282106 control chromosomes, found exclusively in the heterozygous state, and predominantly at a frequency of 0.0022 within the Non-Finnish European subpopulation in the gnomAD database. c.271C>A has been reported in the literature in the compound heterozygous state in at least 10 individuals affected with Congenital Nonprogressive Myopathy With Moebius And Robin Sequences (Carey-Fineman-Ziter Syndrome) from 5 different families in which the variant segregrated with the disease phenotype (e.g. Di Gioia_2017, Hedberg-Oldfors_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Di Gioia_2017). These results indicated that the variant results in a partial loss of function, as observed in a zebrafish model, and has reduced protein expression in in vitro experiments but retains residual function upon overexpression. As a result of these experimental findings, it has been proposed that c.271C>A is likely a hypomorphic variant. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority have classified the variant as either pathogenic (n=4) or likely pathogenic (n=2), and the remaining have classified it as VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003147484	SCV003834914	pathogenic	Carey-Fineman-Ziter syndrome 1	2023-11-20	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001575718	SCV005413930	pathogenic	not provided	2023-10-30	criteria provided, single submitter	clinical testing	PP1, PM2_moderate, PM3, PS3_supporting, PS4
OMIM	RCV000495954	SCV000583972	pathogenic	Congenital nonprogressive myopathy with Moebius and Robin sequences	2019-01-07	no assertion criteria provided	literature only
Baylor Genetics	RCV000495954	SCV001525178	uncertain significance	Congenital nonprogressive myopathy with Moebius and Robin sequences	2019-07-18	flagged submission	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
PreventionGenetics, part of Exact Sciences	RCV003424047	SCV004117201	pathogenic	MYMK-related disorder	2023-12-18	no assertion criteria provided	clinical testing	The MYMK c.271C>A variant is predicted to result in the amino acid substitution p.Pro91Thr. This variant has been reported in the compound heterozygous state in multiple individuals with Carey-Fineman-Ziter syndrome (Figure S1, Di Gioia et al. 2017. PubMed ID: 28681861; Alrohaif et al. 2018. PubMed ID: 29560417; Hedberg-Oldfors et al. 2018. PubMed ID: 30065953). This variant is reported in 0.22% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.