ClinVar Genomic variation as it relates to human health
NM_000256.3(MYBPC3):c.3751T>C (p.Tyr1251His)
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.
Likely pathogenic(1); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000256.3(MYBPC3):c.3751T>C (p.Tyr1251His)
Variation ID: 181020 Accession: VCV000181020.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p11.2 11: 47332135 (GRCh38) [ NCBI UCSC ] 11: 47353686 (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 1, 2016 May 1, 2024 Dec 27, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000256.3:c.3751T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000247.2:p.Tyr1251His missense NC_000011.10:g.47332135A>G NC_000011.9:g.47353686A>G NG_007667.1:g.25568T>C LRG_386:g.25568T>C LRG_386t1:c.3751T>C LRG_386p1:p.Tyr1251His - Protein change
- Y1251H
- Other names
- p.Y1251H:TAT>CAT
- Canonical SPDI
- NC_000011.10:47332134:A: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. |
|||
MYBPC3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3892 | 3909 |
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. |
---|---|---|---|---|
Uncertain significance (2) |
criteria provided, single submitter
|
Jul 18, 2016 | RCV000223863.7 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Mar 30, 2017 | RCV000766379.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 27, 2023 | RCV001850212.5 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Dec 15, 2020 | RCV002345532.2 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Mar 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000208192.12
First in ClinVar: Feb 24, 2015 Last updated: Jul 24, 2016 |
Comment:
A variant of uncertain significance has been identified in the MYBPC3 gene. The Y1251H variant has been reported as a rare variant in one individual … (more)
A variant of uncertain significance has been identified in the MYBPC3 gene. The Y1251H variant has been reported as a rare variant in one individual from an HCM-affected cohort (Lopes et al. 2015); however, additional clinical information, segregation data and functional studies were not provided. Nevertheless, this variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y1251H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. (less)
|
|
Uncertain significance
(Jul 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000712389.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr1251Hi s variant in MYBPC3 has not been previously reported in individuals with cardiom yopathy or … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr1251Hi s variant in MYBPC3 has not been previously reported in individuals with cardiom yopathy or in large population studies. Tyrosine (Tyr) at position 1251 is highl y conserved in mammals and across evolutionarily distant species and the change to Histidine (His) was predicted to be pathogenic using a computational tool cli nically validated by our laboratory. This tool's pathogenic prediction is estima ted to be correct 94% of the time (Jordan 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Tyr1251His variant is uncertain. (less)
Number of individuals with the variant: 1
|
|
Likely pathogenic
(Dec 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002284152.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1251 of the MYBPC3 protein (p.Tyr1251His). … (more)
This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 1251 of the MYBPC3 protein (p.Tyr1251His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25351510, 33782553, 36578016). ClinVar contains an entry for this variant (Variation ID: 181020). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change alters MYBPC3 gene expression (PMID: 34097875). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
Uncertain significance
(Dec 15, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002621278.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.Y1251H variant (also known as c.3751T>C), located in coding exon 33 of the MYBPC3 gene, results from a T to C substitution at nucleotide … (more)
The p.Y1251H variant (also known as c.3751T>C), located in coding exon 33 of the MYBPC3 gene, results from a T to C substitution at nucleotide position 3751. The tyrosine at codon 1251 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet Med, 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(Nov 17, 2011)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280268.1
First in ClinVar: Jun 01, 2016 Last updated: Jun 01, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Tyr1251His (c.3751 T>C) in MYBPC3 Based on the data reviewed below, we consider it a variant of uncertain significance. The variant is novel. It has not been reported previously in association with disease. This is a semi-conservative amino acid substitution, where a neutral, polar Tyrosine residue is exchanged for a positively charged Histidine residue. The Tyrosine at this position is conserved across species. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging, and Mutation Taster predicts the variant to be disease-causing in all three transcripts. Other variants have been reported in association with disease at nearby codons (p.Pro1245Leu, p.Gly1248Arg, p.Ala1255Thr). Legacy names for this variant include Tyr903 and Tyr1250, none of which have any associated literature. In total the variant has not been seen in 6500 published controls and publicly available population datasets. There is no variation at codon 1251 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of May 16, 2013). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of May 16, 2013). (less)
Number of individuals with the variant: 2
|
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 |
---|---|---|---|---|
The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic. | Stafford F | Genome medicine | 2022 | PMID: 36578016 |
Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy. | Suay-Corredera C | The Journal of biological chemistry | 2021 | PMID: 34097875 |
Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation. | Thompson AD | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33782553 |
Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications. | Ingles J | Circulation. Cardiovascular genetics | 2017 | PMID: 28408708 |
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. | Walsh R | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 27532257 |
Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
Text-mined citations for rs730880601 ...
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.