ClinVar Genomic variation as it relates to human health
NM_002465.4(MYBPC1):c.788T>G (p.Leu263Arg)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002465.4(MYBPC1):c.788T>G (p.Leu263Arg)
Variation ID: 635215 Accession: VCV000635215.26
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q23.2 12: 101642541 (GRCh38) [ NCBI UCSC ] 12: 102036319 (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 Jun 30, 2019 May 1, 2024 Feb 23, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_002465.4:c.788T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002456.2:p.Leu263Arg missense NM_001254718.3:c.713T>G NP_001241647.1:p.Leu238Arg missense NM_001254719.3:c.713T>G NP_001241648.1:p.Leu238Arg missense NM_001254720.3:c.677T>G NP_001241649.1:p.Leu226Arg missense NM_001254721.3:c.656T>G NP_001241650.1:p.Leu219Arg missense NM_001254722.3:c.635T>G NP_001241651.1:p.Leu212Arg missense NM_001254723.3:c.674T>G NP_001241652.1:p.Leu225Arg missense NM_001404675.1:c.788T>G NP_001391604.1:p.Leu263Arg missense NM_001404676.1:c.656T>G NP_001391605.1:p.Leu219Arg missense NM_001404677.1:c.578T>G NP_001391606.1:p.Leu193Arg missense NM_001404678.1:c.656T>G NP_001391607.1:p.Leu219Arg missense NM_001404679.1:c.578T>G NP_001391608.1:p.Leu193Arg missense NM_001404680.1:c.635T>G NP_001391609.1:p.Leu212Arg missense NM_001404681.1:c.578T>G NP_001391610.1:p.Leu193Arg missense NM_206819.4:c.788T>G NP_996555.1:p.Leu263Arg missense NM_206820.4:c.713T>G NP_996556.1:p.Leu238Arg missense NM_206821.4:c.713T>G NP_996557.1:p.Leu238Arg missense NC_000012.12:g.101642541T>G NC_000012.11:g.102036319T>G NG_031912.1:g.52611T>G - Protein change
- L263R, L219R, L225R, L226R, L212R, L238R, L193R
- Other names
- -
- Canonical SPDI
- NC_000012.12:101642540:T:G
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
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. |
|||
MYBPC1 | - | - |
GRCh38 GRCh37 |
312 | 360 |
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 (2) |
criteria provided, single submitter
|
Feb 23, 2024 | RCV000786058.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 26, 2023 | RCV001069014.15 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Apr 20, 2023 | RCV000850130.7 | |
Pathogenic (1) |
criteria provided, single submitter
|
Sep 5, 2023 | RCV001267435.7 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Jan 21, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001759044.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment:
Published functional studies demonstrate a damaging effect: decreased binding of the Mmotif to myosin (Shashi et al., 2019) Not observed in large population cohorts (Lek … (more)
Published functional studies demonstrate a damaging effect: decreased binding of the Mmotif to myosin (Shashi et al., 2019) Not observed in large population cohorts (Lek et al., 2016) This variant is associated with the following publications: (PMID: 31264822) (less)
|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Myopathy, congenital, with tremor
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058429.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:31264822, , PS3_S). In silico tool predictions … (more)
Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:31264822, , PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.823, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The same variant was reported as de novo in a similarly affected inidiviual (PMID:31264822, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000635215). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Delayed CNS myelination (present) , Abnormal facial shape (present) , Feeding difficulties in infancy (present) , Gastroesophageal reflux (present) , Global developmental delay (present) , … (more)
Delayed CNS myelination (present) , Abnormal facial shape (present) , Feeding difficulties in infancy (present) , Gastroesophageal reflux (present) , Global developmental delay (present) , Generalized hypotonia (present) , Nasogastric tube feeding in infancy (present) , Tremor (present) (less)
|
|
Pathogenic
(Apr 20, 2023)
|
criteria provided, single submitter
Method: research
|
Myopathy, congenital, with tremor
Affected status: yes
Allele origin:
de novo
|
Duke University Health System Sequencing Clinic, Duke University Health System
Accession: SCV003918919.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
|
|
Pathogenic
(Oct 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017647.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Dec 05, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001234157.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, … (more)
For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individuals with tremor and muscle weakness (PMID: 31264822). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 635215). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with arginine at codon 263 of the MYBPC1 protein (p.Leu263Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. (less)
|
|
Pathogenic
(Feb 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
MYBPC1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004105959.2
First in ClinVar: Nov 20, 2023 Last updated: Mar 16, 2024 |
Comment:
The MYBPC1 c.788T>G variant is predicted to result in the amino acid substitution p.Leu263Arg. This variant was reported to have occurred de novo in two … (more)
The MYBPC1 c.788T>G variant is predicted to result in the amino acid substitution p.Leu263Arg. This variant was reported to have occurred de novo in two different families in individuals with muscle weakness, tremors and hypotonia, and was inherited by an affected daughter in one family. Functional in vitro studies demonstrated this variants impairs myosin binding (Shashi. 2019. PubMed ID: 31264822). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
Pathogenic
(Sep 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001445616.5
First in ClinVar: Nov 21, 2020 Last updated: May 01, 2024 |
Comment:
The c.788T>G (p.L263R) alteration is located in coding exon 11 of the MYBPC1 gene. This alteration results from a T to G substitution at nucleotide … (more)
The c.788T>G (p.L263R) alteration is located in coding exon 11 of the MYBPC1 gene. This alteration results from a T to G substitution at nucleotide position 788, causing the leucine (L) at amino acid position 263 to be replaced by an arginine (R). for autosomal dominant MYBPC1-related congenital myopathy with tremor; however, its clinical significance for autosomal dominant MYBPC1-related distal arthrogryposis is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation multiple individuals with features consistent with MYBC1-related congenital myopathy with tremor (Shashi, 2019). This amino acid position is highly conserved in available vertebrate species. The p.L263R amino acid is located in the M-motif for the protein, which is involved in binding myosin and the formation of actomyosin cross-bridges during muscle contraction (Shashi, 2019). Multiple heterozygous alterations in the M-motif have been reported in patients with myopathy and tremors (Shashi, 2019; Stavusis, 2019). In vitro analysis demonstrated that recombinant protein with the p.L263R alteration had decreased myosin binding and decreased stability when compared to wild type protein (Shashi, 2019). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
Likely pathogenic
(Apr 05, 2017)
|
no assertion criteria provided
Method: clinical testing
|
MYBPC1-related condition
Affected status: yes
Allele origin:
de novo,
paternal
|
Genomics And Bioinformatics Analysis Resource, Columbia University
Accession: SCV000924697.2
First in ClinVar: Jun 30, 2019 Last updated: Sep 23, 2023 |
Observation 1:
Age: 40-49 years
Sex: male
Ethnicity/Population group: Korean
Observation 2:
Age: 0-9 years
Sex: female
Ethnicity/Population group: Korean
Observation 3:
Age: 0-9 years
Sex: female
Ethnicity/Population group: Caucasian
|
|
Pathogenic
(Mar 10, 2023)
|
no assertion criteria provided
Method: literature only
|
CONGENITAL MYOPATHY 16
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000992294.2
First in ClinVar: Sep 09, 2019 Last updated: Mar 18, 2023 |
Comment on evidence:
In a 9-year-old Caucasian girl (patient 1) and in a Korean father and daughter (patients 4 and 3) with congenital myopathy-16 (CMYP16; 618524), Shashi et … (more)
In a 9-year-old Caucasian girl (patient 1) and in a Korean father and daughter (patients 4 and 3) with congenital myopathy-16 (CMYP16; 618524), Shashi et al. (2019) identified a heterozygous c.788T-G transversion (c.788T-G, NM_002465.3) in the MYBPC1 gene, resulting in a leu263-to-arg (L263R) substitution at a highly conserved residue in the N-terminal M-motif. The mutation occurred de novo in patient 1 and in the Korean father. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. In vitro functional expression studies showed that the L263R mutation resulted in significantly decreased binding of the M-motif to myosin compared to wildtype, which likely impairs the formation of actomyosin cross-bridges during muscle contraction. Actin binding was similar to wildtype. Molecular modeling and dynamic studies showed that the L263R mutation resulted in decreased stability compared to wildtype. (less)
|
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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Heterozygous variants in MYBPC1 are associated with an expanded neuromuscular phenotype beyond arthrogryposis. | Shashi V | Human mutation | 2019 | PMID: 31264822 |
Novel mutations in MYBPC1 are associated with myogenic tremor and mild myopathy. | Stavusis J | Annals of neurology | 2019 | PMID: 31025394 |
Text-mined citations for rs1565943228 ...
HelpRecord last updated May 01, 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.