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).
ClinVar Genomic variation as it relates to human health
NM_001080483.3(MYMK):c.271C>A (p.Pro91Thr)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(12)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
12
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001080483.3(MYMK):c.271C>A (p.Pro91Thr)
Variation ID: 430839 Accession: VCV000430839.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.2 9: 133519002 (GRCh38) [ NCBI UCSC ] 9: 136384124 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jan 10, 2019 Nov 24, 2024 Nov 13, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001080483.3:c.271C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001073952.1:p.Pro91Thr missense NC_000009.12:g.133519002G>T NC_000009.11:g.136384124G>T - Protein change
- P91T
- Other names
- -
- Canonical SPDI
- NC_000009.12:133519001:G:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00140 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00124
1000 Genomes Project 30x 0.00125
The Genome Aggregation Database (gnomAD) 0.00125
Exome Aggregation Consortium (ExAC) 0.00128
Trans-Omics for Precision Medicine (TOPMed) 0.00133
1000 Genomes Project 0.00140
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00177
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| MYMK | - | - |
GRCh38 GRCh37 |
58 | 103 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 2, 2022 | RCV000495954.19 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 13, 2024 | RCV001575718.7 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Nov 20, 2023 | RCV003147484.6 | |
|
MYMK-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Dec 18, 2023 | RCV003424047.6 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Dec 03, 2018)
|
criteria provided, single submitter
Method: research
|
Carey-Fineman-Ziter syndrome 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164470.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
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. … (more)
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). (less)
|
|
|
Pathogenic
(Jun 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Carey-Fineman-Ziter syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV001451455.1
First in ClinVar: Dec 23, 2020 Last updated: Dec 23, 2020 |
Comment:
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 … (more)
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. (less)
|
|
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Likely pathogenic
(Jun 30, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Carey-Fineman-Ziter syndrome 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017854.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 30, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Carey-Fineman-Ziter syndrome 1
Affected status: yes
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503610.2
First in ClinVar: Apr 28, 2022 Last updated: Apr 15, 2024 |
Comment:
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 … (more)
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. (less)
|
|
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Likely pathogenic
(Nov 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001802767.4
First in ClinVar: Aug 21, 2021 Last updated: Nov 24, 2024 |
Comment:
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 … (more)
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) (less)
|
|
|
Pathogenic
(May 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Carey-Fineman-Ziter syndrome 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV001244964.3
First in ClinVar: May 04, 2020 Last updated: Nov 24, 2024 |
Comment:
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 … (more)
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 (less)
|
|
|
Pathogenic
(Dec 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Congenital nonprogressive myopathy with Moebius and Robin sequences
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002819542.1
First in ClinVar: Jan 15, 2023 Last updated: Jan 15, 2023 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Nov 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Carey-Fineman-Ziter syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003834914.2
First in ClinVar: Mar 11, 2023 Last updated: Dec 24, 2023 |
|
|
|
Pathogenic
(Oct 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413930.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP1, PM2_moderate, PM3, PS3_supporting, PS4
Number of individuals with the variant: 1
|
|
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Pathogenic
(Jan 07, 2019)
|
no assertion criteria provided
Method: literature only
|
CAREY-FINEMAN-ZITER SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000583972.2
First in ClinVar: Jul 23, 2017 Last updated: Jan 10, 2019 |
Comment on evidence:
In 7 patients from 4 unrelated families with Carey-Fineman-Ziter syndrome (CFZS; 254940), Di Gioia et al. (2017) identified compound heterozygous missense mutations in the MYMK … (more)
In 7 patients from 4 unrelated families with Carey-Fineman-Ziter syndrome (CFZS; 254940), Di Gioia et al. (2017) identified compound heterozygous missense mutations in the MYMK gene: all patients carried a heterozygous c.271C-A transversion in exon 3, resulting in a pro91-to-thr (P91T) substitution in transmembrane domain (TM) 4 on 1 allele. Haplotype analysis suggested a founder effect. The mutation on the other allele differed in each family. Family 1 had a c.553T-C transition in exon 5, resulting in a cys185-to-arg (C185R; 615345.0002) substitution at a conserved residue in transmembrane domain 7; this family was originally reported by Carey et al. (1982). Affected members of families 2 and 3 had a c.298G-A transition in exon 3, resulting in a gly100-to-ser (G100S; 615345.0003) substitution in TM4 on the other allele. The G100S mutation, which occurred at a CpG dinucleotide, arose without a founder effect. The patient from family 4 had a c.2T-A transversion in exon 1 (615345.0004), resulting in disruption of the methionine initiation codon (p.M1?; 615345.0004). The mutations in the first 3 families were found by whole-exome sequencing and confirmed by Sanger sequencing; mutations in the other family were found by sequencing the MYMK gene in over 300 additional probands with similar phenotypes. All mutations segregated with the disorder in the families. The variants were filtered against various databases, including the 1000 Genomes Project, Exome Variant Server, and ExAC databases. Only P91T was found at a low frequency (0.0013) in the ExAC database: this mutation was reported in the homozygous state in 1 individual with no declared phenotype who was not recontactable. In vitro functional expression studies suggested that the P91T mutant protein was hypomorphic and able to induce fusion in transfected cells almost as well as the wildtype protein; however, expression of the mutant protein was decreased. The 3 other mutations were demonstrated to be null alleles. By whole-exome sequencing in a 69-year-old British man with CFZS, Alrohaif et al. (2018) identified compound heterozygosity for the P91T and C185R mutations in the MYMK gene. (less)
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Pathogenic
(Dec 18, 2023)
|
no assertion criteria provided
Method: clinical testing
|
MYMK-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004117201.3
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Jul 18, 2019)
|
Flagged submission
flagged submission
Method: clinical testing
Reason: New submission from submitter that appears to have been intended to update this older submission
Source: ClinGen
|
Carey-Fineman-Ziter syndrome 1
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV001525178.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
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| click to load more click to collapse | |||||
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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
Comment:
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.
Comment:
PP1, PM2_moderate, PM3, PS3_supporting, PS4
Comment:
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.
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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).
Comment:
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.
Comment:
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.
Comment:
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)
Comment:
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
Comment:
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.
Comment:
PP1, PM2_moderate, PM3, PS3_supporting, PS4
Comment:
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.
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System. | Australian Genomics Health Alliance Acute Care Flagship | JAMA | 2020 | PMID: 32573669 |
| Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness. | Töpf A | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32528171 |
| Carey-Fineman-Ziter syndrome with mutations in the myomaker gene and muscle fiber hypertrophy. | Hedberg-Oldfors C | Neurology. Genetics | 2018 | PMID: 30065953 |
| Whole-exome sequencing identifies mutations in MYMK in a mild form of Carey-Fineman-Ziter syndrome. | Alrohaif H | Neurology. Genetics | 2018 | PMID: 29560417 |
| A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome. | Di Gioia SA | Nature communications | 2017 | PMID: 28681861 |
| The Robin sequence as a consequence of malformation, dysplasia, and neuromuscular syndromes. | Carey JC | The Journal of pediatrics | 1982 | PMID: 7131178 |
Text-mined citations for rs137868995 ...
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Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.