The p.Glu22Lys variant in MYL2 has been reported in >25 individuals with HCM and segregated in >20 affected relatives (Ãlvarez-Acosta 2014, Claes 2015, Poetter 1996, Kabaeva 2002, Walsh 2017, LMM data). This variant reportedly did not segregate with disease in several affected relatives, though at least 4 of these individuals were reported to have additional risk factors or carried additional variants in cardiomyopathy related genes (Alvarez-Acosta 2014, Claes 2015). This variant has also been identified in 5/251472 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and had been reported in ClinVar (Variation ID #14065). Multiple in vitro and transgenic animal studies have shown that the p.Glu22Lys variant impacts protein function (Levine 1998, Roopnarine 2003, Szczesna 2001, Szczsna-Cordary 2004, Szczsna-Cordary 2007). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Moderate, PM2.
ClinVar Genomic variation as it relates to human health
NM_000432.4(MYL2):c.64G>A (p.Glu22Lys)
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.
(23)
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
23
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000432.4(MYL2):c.64G>A (p.Glu22Lys)
Variation ID: 14065 Accession: VCV000014065.49
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q24.11 12: 110919133 (GRCh38) [ NCBI UCSC ] 12: 111356937 (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 Apr 4, 2013 Oct 20, 2024 Feb 5, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000432.4:c.64G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000423.2:p.Glu22Lys missense NC_000012.12:g.110919133C>T NC_000012.11:g.111356937C>T NG_007554.1:g.6445G>A NG_065206.1:g.281C>T LRG_393:g.6445G>A LRG_393t1:c.64G>A LRG_393p1:p.Glu22Lys P10916:p.Glu22Lys - Protein change
- E22K
- Other names
-
p.E22K:GAA>AAA
- Canonical SPDI
- NC_000012.12:110919132:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
probably has functional consequence
-
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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
- 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. |
|||
| LOC114827850 | - | - | - | GRCh38 | - | 129 |
| MYL2 | - | - |
GRCh38 GRCh37 |
436 | 571 | |
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 (7) |
criteria provided, multiple submitters, no conflicts
|
Jan 20, 2024 | RCV000015109.43 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Dec 13, 2022 | RCV000158914.29 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 27, 2015 | RCV000234985.4 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 5, 2024 | RCV000768488.13 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 21, 2023 | RCV001170438.11 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jul 25, 2023 | RCV002354163.6 | |
|
MYL2-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 25, 2023 | RCV004532354.1 |
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
(Jul 15, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 10
Affected status: yes
Allele origin:
germline
|
Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000299269.1
First in ClinVar: Sep 09, 2016 Last updated: Sep 09, 2016 |
|
|
|
Pathogenic
(Jul 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 10
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000744074.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
|
Pathogenic
(Sep 21, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 10
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745544.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, University of Leuven
Accession: SCV000886792.1
First in ClinVar: May 02, 2019 Last updated: May 02, 2019 |
|
|
|
Pathogenic
(Oct 18, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV000927440.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019
Comment:
Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel
|
|
|
|
Pathogenic
(Sep 24, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000203862.4
First in ClinVar: Jan 31, 2015 Last updated: Jul 03, 2020 |
Comment:
The p.Glu22Lys variant in MYL2 has been reported in >25 individuals with HCM and segregated in >20 affected relatives (Ãlvarez-Acosta 2014, Claes 2015, Poetter 1996, … (more)
The p.Glu22Lys variant in MYL2 has been reported in >25 individuals with HCM and segregated in >20 affected relatives (Ãlvarez-Acosta 2014, Claes 2015, Poetter 1996, Kabaeva 2002, Walsh 2017, LMM data). This variant reportedly did not segregate with disease in several affected relatives, though at least 4 of these individuals were reported to have additional risk factors or carried additional variants in cardiomyopathy related genes (Alvarez-Acosta 2014, Claes 2015). This variant has also been identified in 5/251472 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and had been reported in ClinVar (Variation ID #14065). Multiple in vitro and transgenic animal studies have shown that the p.Glu22Lys variant impacts protein function (Levine 1998, Roopnarine 2003, Szczesna 2001, Szczsna-Cordary 2004, Szczsna-Cordary 2007). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Moderate, PM2. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000208849.10
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Haplotype analysis suggests this variant is a founder mutation in the Dutch population (Claes et al., 2016); Not observed at significant frequency in large population … (more)
Haplotype analysis suggests this variant is a founder mutation in the Dutch population (Claes et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that E22K alters MYL2 function (Szczesna et al., 2001; Szczesna-Cordary et al., 2004; Roopnarine et al., 2003; Szczesna-Cordary et al., 2007, Farman et al., 2014; Zhang et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14594949, 16751284, 9724616, 31513939, 17606808, 12668451, 25324513, 8673105, 12404107, 21310275, 27532257, 28166811, 28138913, 27435932, 28606303, 26497160, 28790153, 16076902, 30605904, 21896538, 10948063, 30847666, 33673806, 32665702, 32880476, 33087929, 33662488, 11102452, 33548158) (less)
|
|
|
Pathogenic
(Dec 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026231.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PS4, PP3, PM2_SUP, PS3
|
|
|
Pathogenic
(Apr 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
MYL2-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004117554.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MYL2 c.64G>A variant is predicted to result in the amino acid substitution p.Glu22Lys. This variant was reported in multiple individuals with hypertrophic cardiomyopathy (see … (more)
The MYL2 c.64G>A variant is predicted to result in the amino acid substitution p.Glu22Lys. This variant was reported in multiple individuals with hypertrophic cardiomyopathy (see for example, Poetter et al. 1996. PubMed ID: 8673105; Robyns et al. 2020. PubMed ID: 31513939; Walsh et al. 2017. PubMed ID: 27532257). Multiple functional studies suggest this variant alters protein function (see for example, Zhang et al. 2021. PubMed ID: 33548158; Szczesna-Cordary et al. 2007. PubMed ID: 17606808). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-111356937-C-T). This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Jan 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy 10
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000549155.9
First in ClinVar: Sep 09, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 22 of the MYL2 protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 22 of the MYL2 protein (p.Glu22Lys). This variant is present in population databases (rs104894368, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8673105, 12404107, 26497160, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14065). 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. Experimental studies have shown that this missense change affects MYL2 function (PMID: 12668451, 14594949, 16076902, 17606808, 25324513, 26497160). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812326.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in MYL2 is predicted to replace glutamic acid with lysine at codon 22, p.(Glu22Lys). The glutamic acid residue is highly conserved (100 … (more)
This sequence change in MYL2 is predicted to replace glutamic acid with lysine at codon 22, p.(Glu22Lys). The glutamic acid residue is highly conserved (100 vertebrates, UCSC). There is a small physicochemical difference between glutamic acid and lysine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.006% (2/34,590 alleles) in the Latino/Admixed American population. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio = 8.4, 95 % CI:1.64 to 43.5; VariantFX Cardiac Allele Frequencies, DECIPHER vs gnomAD v2.1 Latino/Admixed American population). The variant has been reported to segregate with cardiomyopathy across multiple affected families and is associated with incomplete penetrance and later onset of hypertrophic cardiomyopathy (PMID: 26497160). In vitro functional assays and transgenic mouse models showed a significant change in the calcium-binding properties for this variant indicating it impacts protein function (PMID: 11102452, 16076902, 17606808, 14594949, 12668451). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.714). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PP3, PS3_Moderate, PS4_Moderate (less)
|
|
|
Pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002501723.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
Likely pathogenic
(Mar 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333018.3
First in ClinVar: May 31, 2020 Last updated: Mar 11, 2023 |
|
|
|
Pathogenic
(Mar 21, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiomyopathy
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001351143.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamic acid with lysine at codon 22 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces glutamic acid with lysine at codon 22 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant affects protein function by altering calcium sensitivity of force and ATPase activity in vitro and in transgenic mice (PMID: 12668451, 14594949, 16076902, 17606808, 25324513). This variant has been reported in over 40 individuals affected with hypertrophic cardiomyopathy from over 20 families (PMID: 8673105, 12404107, 26497160, 27532257; ClinVar SCV000203862.4). This variant has shown reduced penetrance and late-onset disease with moderate symptoms in some individuals. A study of 38 carriers from 14 Dutch families has suggested that this variant together with the presence of an additional risk factor, such as hypertension, contributes to the development of hypertrophic cardiomyopathy (PMID: 26497160). This variant has been identified in 5/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypertrophic cardiomyopathy
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004845869.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
The c.64G>A (p.Glu22Lys) variant of the MYL2 gene replaces glutamic acid with lysine at codon 22 of the MYL2 protein. This variant has been reported … (more)
The c.64G>A (p.Glu22Lys) variant of the MYL2 gene replaces glutamic acid with lysine at codon 22 of the MYL2 protein. This variant has been reported in more than 40 unrelated individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 8673105, 12404107, 26497160, 27532257), and has been shown to segregate with HCM in several families (PMID: 27532257, 12404107). This variant has shown incomplete penetrance and late-onset disease with moderate symptoms in some individuals. A study of 38 heterozygous individuals from 14 Dutch families has suggested that this variant is a founder variant with shared haplotype in the Netherlands, and that the presence of an additional risk factor, such as hypertension, contributes to the development of HCM (PMID: 26497160). Functional studies have shown that this variant affects MYL2 protein function by altering calcium sensitivity of force and ATPase activity in vitro and in transgenic mice (PMID: 12668451, 14594949, 16076902, 17606808, 25324513). Computational evidence supports a deleterious effect on the protein structure and function (REVEL score 0.714). This variant has been identified in 5/251472 chromosomes in the general population (gnomAD). Based on these evidence, the c.64G>A (p.Glu22Lys) variant of the MYL2 gene is interpreted as pathogenic. (less)
Number of individuals with the variant: 7
|
|
|
Likely pathogenic
(Jul 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002655548.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.E22K variant (also known as c.64G>A), located in coding exon 2 of the MYL2 gene, results from a G to A substitution at nucleotide … (more)
The p.E22K variant (also known as c.64G>A), located in coding exon 2 of the MYL2 gene, results from a G to A substitution at nucleotide position 64. The glutamic acid at codon 22 is replaced by lysine, an amino acid with similar properties. This alteration has been previously detected in numerous hypertrophic cardiomyopathy (HCM) cohorts and has been shown to segregate with HCM in several families (Poetter K et al. Nat. Genet., 1996 May;13:63-9; Kabaeva ZT et al. Eur. J. Hum. Genet., 2002 Nov;10:741-8; Lopes LR et al. Heart, 2015 Feb;101:294-301; Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is a founder mutation with shared haplotype in the Netherlands; however, the presence of this allele in unaffected relatives and the existence of additional risk factors in many of the affected carriers suggests this allele exhibits reduced penetrance and may not cause disease on its own (Claes GR et al. Eur. Heart J., 2016 06;37:1815-22). Multiple in vitro functional studies suggest this alteration may impact protein function, but adult transgenic mice expressing E22K do not exhibit detectable cardiac hypertrophy (Sanbe A et al. Circ. Res., 2000 Aug;87:296-302; Roopnarine O. Biophys. J., 2003 Apr;84:2440-9; Szczesna-Cordary D et al. J. Cell. Sci., 2005 Aug;118:3675-83; Farman GP et al. J. Appl. Physiol., 2014 Dec;117:1471-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, it may represent a risk factor or a milder allele that presents with incomplete penetrance. (less)
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002585422.15
First in ClinVar: Oct 22, 2022 Last updated: Oct 20, 2024 |
Comment:
MYL2: PP1:Strong, PM1, PM2, PS4:Moderate
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 27, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Death in early adulthood
Affected status: yes
Allele origin:
unknown
|
Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences
Study: HCIFS-Postmortem genetic screening project
Accession: SCV000263119.1 First in ClinVar: Jul 15, 2016 Last updated: Jul 15, 2016 |
Clinical Features:
Death in early adulthood (present)
Age: 20-29 years
Sex: male
Ethnicity/Population group: Hispanic Americans
Tissue: Blood
|
|
|
Pathogenic
(Nov 01, 2002)
|
no assertion criteria provided
Method: literature only
|
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 10
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035366.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 16, 2018 |
Comment on evidence:
In 2 affected brothers and an unrelated individual from 2 unrelated families segregating hypertrophic cardiomyopathy (CMH10; 608758), who displayed unusual mid-left ventricular chamber thickening on … (more)
In 2 affected brothers and an unrelated individual from 2 unrelated families segregating hypertrophic cardiomyopathy (CMH10; 608758), who displayed unusual mid-left ventricular chamber thickening on echocardiography, Poetter et al. (1996) identified heterozygosity for a glu22-to-lys (E22K) substitution at an evolutionarily conserved residue in the MYL2 gene product. The mutation was not found in 378 control chromosomes or in 790 chromosomes from CMH patients with diverse ethnic backgrounds. Kabaeva et al. (2002) identified the E22K mutation, resulting from a heterozygous 64G-A transition in the MYL2 gene, in 7 members (4 affected and 3 with 'uncertain' phenotypes) of a family with CMH10 who had mild to moderate septal hypertrophy, a late onset of clinical manifestations, and a benign disease course and prognosis. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001918311.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953668.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Hypertrophic cardiomyopathy 10
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733135.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
|
|
|
not provided
(Mar 26, 2012)
|
no classification provided
Method: curation
|
Familial hypertrophic cardiomyopathy 10
Affected status: not provided
Allele origin:
germline
|
Leiden Muscular Dystrophy (MYL2)
Accession: SCV000045755.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
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Comment:
Comment:
Haplotype analysis suggests this variant is a founder mutation in the Dutch population (Claes et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that E22K alters MYL2 function (Szczesna et al., 2001; Szczesna-Cordary et al., 2004; Roopnarine et al., 2003; Szczesna-Cordary et al., 2007, Farman et al., 2014; Zhang et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14594949, 16751284, 9724616, 31513939, 17606808, 12668451, 25324513, 8673105, 12404107, 21310275, 27532257, 28166811, 28138913, 27435932, 28606303, 26497160, 28790153, 16076902, 30605904, 21896538, 10948063, 30847666, 33673806, 32665702, 32880476, 33087929, 33662488, 11102452, 33548158)
Comment:
PS4, PP3, PM2_SUP, PS3
Comment:
The MYL2 c.64G>A variant is predicted to result in the amino acid substitution p.Glu22Lys. This variant was reported in multiple individuals with hypertrophic cardiomyopathy (see for example, Poetter et al. 1996. PubMed ID: 8673105; Robyns et al. 2020. PubMed ID: 31513939; Walsh et al. 2017. PubMed ID: 27532257). Multiple functional studies suggest this variant alters protein function (see for example, Zhang et al. 2021. PubMed ID: 33548158; Szczesna-Cordary et al. 2007. PubMed ID: 17606808). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-111356937-C-T). This variant is interpreted as pathogenic.
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 22 of the MYL2 protein (p.Glu22Lys). This variant is present in population databases (rs104894368, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8673105, 12404107, 26497160, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14065). 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. Experimental studies have shown that this missense change affects MYL2 function (PMID: 12668451, 14594949, 16076902, 17606808, 25324513, 26497160). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change in MYL2 is predicted to replace glutamic acid with lysine at codon 22, p.(Glu22Lys). The glutamic acid residue is highly conserved (100 vertebrates, UCSC). There is a small physicochemical difference between glutamic acid and lysine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.006% (2/34,590 alleles) in the Latino/Admixed American population. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio = 8.4, 95 % CI:1.64 to 43.5; VariantFX Cardiac Allele Frequencies, DECIPHER vs gnomAD v2.1 Latino/Admixed American population). The variant has been reported to segregate with cardiomyopathy across multiple affected families and is associated with incomplete penetrance and later onset of hypertrophic cardiomyopathy (PMID: 26497160). In vitro functional assays and transgenic mouse models showed a significant change in the calcium-binding properties for this variant indicating it impacts protein function (PMID: 11102452, 16076902, 17606808, 14594949, 12668451). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.714). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PP3, PS3_Moderate, PS4_Moderate
Comment:
This missense variant replaces glutamic acid with lysine at codon 22 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant affects protein function by altering calcium sensitivity of force and ATPase activity in vitro and in transgenic mice (PMID: 12668451, 14594949, 16076902, 17606808, 25324513). This variant has been reported in over 40 individuals affected with hypertrophic cardiomyopathy from over 20 families (PMID: 8673105, 12404107, 26497160, 27532257; ClinVar SCV000203862.4). This variant has shown reduced penetrance and late-onset disease with moderate symptoms in some individuals. A study of 38 carriers from 14 Dutch families has suggested that this variant together with the presence of an additional risk factor, such as hypertension, contributes to the development of hypertrophic cardiomyopathy (PMID: 26497160). This variant has been identified in 5/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The c.64G>A (p.Glu22Lys) variant of the MYL2 gene replaces glutamic acid with lysine at codon 22 of the MYL2 protein. This variant has been reported in more than 40 unrelated individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 8673105, 12404107, 26497160, 27532257), and has been shown to segregate with HCM in several families (PMID: 27532257, 12404107). This variant has shown incomplete penetrance and late-onset disease with moderate symptoms in some individuals. A study of 38 heterozygous individuals from 14 Dutch families has suggested that this variant is a founder variant with shared haplotype in the Netherlands, and that the presence of an additional risk factor, such as hypertension, contributes to the development of HCM (PMID: 26497160). Functional studies have shown that this variant affects MYL2 protein function by altering calcium sensitivity of force and ATPase activity in vitro and in transgenic mice (PMID: 12668451, 14594949, 16076902, 17606808, 25324513). Computational evidence supports a deleterious effect on the protein structure and function (REVEL score 0.714). This variant has been identified in 5/251472 chromosomes in the general population (gnomAD). Based on these evidence, the c.64G>A (p.Glu22Lys) variant of the MYL2 gene is interpreted as pathogenic.
Comment:
The p.E22K variant (also known as c.64G>A), located in coding exon 2 of the MYL2 gene, results from a G to A substitution at nucleotide position 64. The glutamic acid at codon 22 is replaced by lysine, an amino acid with similar properties. This alteration has been previously detected in numerous hypertrophic cardiomyopathy (HCM) cohorts and has been shown to segregate with HCM in several families (Poetter K et al. Nat. Genet., 1996 May;13:63-9; Kabaeva ZT et al. Eur. J. Hum. Genet., 2002 Nov;10:741-8; Lopes LR et al. Heart, 2015 Feb;101:294-301; Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is a founder mutation with shared haplotype in the Netherlands; however, the presence of this allele in unaffected relatives and the existence of additional risk factors in many of the affected carriers suggests this allele exhibits reduced penetrance and may not cause disease on its own (Claes GR et al. Eur. Heart J., 2016 06;37:1815-22). Multiple in vitro functional studies suggest this alteration may impact protein function, but adult transgenic mice expressing E22K do not exhibit detectable cardiac hypertrophy (Sanbe A et al. Circ. Res., 2000 Aug;87:296-302; Roopnarine O. Biophys. J., 2003 Apr;84:2440-9; Szczesna-Cordary D et al. J. Cell. Sci., 2005 Aug;118:3675-83; Farman GP et al. J. Appl. Physiol., 2014 Dec;117:1471-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, it may represent a risk factor or a milder allele that presents with incomplete penetrance.
Comment:
MYL2: PP1:Strong, PM1, PM2, PS4:Moderate
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
probably has functional consequence
|
Leiden Muscular Dystrophy (MYL2)
Accession: SCV000045755.1
|
|
Comment:
The p.Glu22Lys variant in MYL2 has been reported in >25 individuals with HCM and segregated in >20 affected relatives (Ãlvarez-Acosta 2014, Claes 2015, Poetter 1996, Kabaeva 2002, Walsh 2017, LMM data). This variant reportedly did not segregate with disease in several affected relatives, though at least 4 of these individuals were reported to have additional risk factors or carried additional variants in cardiomyopathy related genes (Alvarez-Acosta 2014, Claes 2015). This variant has also been identified in 5/251472 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and had been reported in ClinVar (Variation ID #14065). Multiple in vitro and transgenic animal studies have shown that the p.Glu22Lys variant impacts protein function (Levine 1998, Roopnarine 2003, Szczesna 2001, Szczsna-Cordary 2004, Szczsna-Cordary 2007). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PS4, PP1_Strong, PS3_Moderate, PM2.
Comment:
Haplotype analysis suggests this variant is a founder mutation in the Dutch population (Claes et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that E22K alters MYL2 function (Szczesna et al., 2001; Szczesna-Cordary et al., 2004; Roopnarine et al., 2003; Szczesna-Cordary et al., 2007, Farman et al., 2014; Zhang et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14594949, 16751284, 9724616, 31513939, 17606808, 12668451, 25324513, 8673105, 12404107, 21310275, 27532257, 28166811, 28138913, 27435932, 28606303, 26497160, 28790153, 16076902, 30605904, 21896538, 10948063, 30847666, 33673806, 32665702, 32880476, 33087929, 33662488, 11102452, 33548158)
Comment:
PS4, PP3, PM2_SUP, PS3
Comment:
The MYL2 c.64G>A variant is predicted to result in the amino acid substitution p.Glu22Lys. This variant was reported in multiple individuals with hypertrophic cardiomyopathy (see for example, Poetter et al. 1996. PubMed ID: 8673105; Robyns et al. 2020. PubMed ID: 31513939; Walsh et al. 2017. PubMed ID: 27532257). Multiple functional studies suggest this variant alters protein function (see for example, Zhang et al. 2021. PubMed ID: 33548158; Szczesna-Cordary et al. 2007. PubMed ID: 17606808). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-111356937-C-T). This variant is interpreted as pathogenic.
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 22 of the MYL2 protein (p.Glu22Lys). This variant is present in population databases (rs104894368, gnomAD 0.006%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 8673105, 12404107, 26497160, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14065). 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. Experimental studies have shown that this missense change affects MYL2 function (PMID: 12668451, 14594949, 16076902, 17606808, 25324513, 26497160). For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change in MYL2 is predicted to replace glutamic acid with lysine at codon 22, p.(Glu22Lys). The glutamic acid residue is highly conserved (100 vertebrates, UCSC). There is a small physicochemical difference between glutamic acid and lysine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.006% (2/34,590 alleles) in the Latino/Admixed American population. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio = 8.4, 95 % CI:1.64 to 43.5; VariantFX Cardiac Allele Frequencies, DECIPHER vs gnomAD v2.1 Latino/Admixed American population). The variant has been reported to segregate with cardiomyopathy across multiple affected families and is associated with incomplete penetrance and later onset of hypertrophic cardiomyopathy (PMID: 26497160). In vitro functional assays and transgenic mouse models showed a significant change in the calcium-binding properties for this variant indicating it impacts protein function (PMID: 11102452, 16076902, 17606808, 14594949, 12668451). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.714). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PP3, PS3_Moderate, PS4_Moderate
Comment:
This missense variant replaces glutamic acid with lysine at codon 22 of the MYL2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant affects protein function by altering calcium sensitivity of force and ATPase activity in vitro and in transgenic mice (PMID: 12668451, 14594949, 16076902, 17606808, 25324513). This variant has been reported in over 40 individuals affected with hypertrophic cardiomyopathy from over 20 families (PMID: 8673105, 12404107, 26497160, 27532257; ClinVar SCV000203862.4). This variant has shown reduced penetrance and late-onset disease with moderate symptoms in some individuals. A study of 38 carriers from 14 Dutch families has suggested that this variant together with the presence of an additional risk factor, such as hypertension, contributes to the development of hypertrophic cardiomyopathy (PMID: 26497160). This variant has been identified in 5/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The c.64G>A (p.Glu22Lys) variant of the MYL2 gene replaces glutamic acid with lysine at codon 22 of the MYL2 protein. This variant has been reported in more than 40 unrelated individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 8673105, 12404107, 26497160, 27532257), and has been shown to segregate with HCM in several families (PMID: 27532257, 12404107). This variant has shown incomplete penetrance and late-onset disease with moderate symptoms in some individuals. A study of 38 heterozygous individuals from 14 Dutch families has suggested that this variant is a founder variant with shared haplotype in the Netherlands, and that the presence of an additional risk factor, such as hypertension, contributes to the development of HCM (PMID: 26497160). Functional studies have shown that this variant affects MYL2 protein function by altering calcium sensitivity of force and ATPase activity in vitro and in transgenic mice (PMID: 12668451, 14594949, 16076902, 17606808, 25324513). Computational evidence supports a deleterious effect on the protein structure and function (REVEL score 0.714). This variant has been identified in 5/251472 chromosomes in the general population (gnomAD). Based on these evidence, the c.64G>A (p.Glu22Lys) variant of the MYL2 gene is interpreted as pathogenic.
Comment:
The p.E22K variant (also known as c.64G>A), located in coding exon 2 of the MYL2 gene, results from a G to A substitution at nucleotide position 64. The glutamic acid at codon 22 is replaced by lysine, an amino acid with similar properties. This alteration has been previously detected in numerous hypertrophic cardiomyopathy (HCM) cohorts and has been shown to segregate with HCM in several families (Poetter K et al. Nat. Genet., 1996 May;13:63-9; Kabaeva ZT et al. Eur. J. Hum. Genet., 2002 Nov;10:741-8; Lopes LR et al. Heart, 2015 Feb;101:294-301; Alejandra Restrepo-Cordoba M et al. J Cardiovasc Transl Res, 2017 Feb;10:35-46; Walsh R et al. Genet. Med., 2017 02;19:192-203). This variant is a founder mutation with shared haplotype in the Netherlands; however, the presence of this allele in unaffected relatives and the existence of additional risk factors in many of the affected carriers suggests this allele exhibits reduced penetrance and may not cause disease on its own (Claes GR et al. Eur. Heart J., 2016 06;37:1815-22). Multiple in vitro functional studies suggest this alteration may impact protein function, but adult transgenic mice expressing E22K do not exhibit detectable cardiac hypertrophy (Sanbe A et al. Circ. Res., 2000 Aug;87:296-302; Roopnarine O. Biophys. J., 2003 Apr;84:2440-9; Szczesna-Cordary D et al. J. Cell. Sci., 2005 Aug;118:3675-83; Farman GP et al. J. Appl. Physiol., 2014 Dec;117:1471-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic; however, it may represent a risk factor or a milder allele that presents with incomplete penetrance.
Comment:
MYL2: PP1:Strong, PM1, PM2, PS4:Moderate
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory. | Stava TT | European journal of preventive cardiology | 2022 | PMID: 35653365 |
| Not Only Diagnostic Yield: Whole-Exome Sequencing in Infantile Cardiomyopathies Impacts on Clinical and Family Management. | Pezzoli L | Journal of cardiovascular development and disease | 2021 | PMID: 35050212 |
| Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients. | Hathaway J | BMC cardiovascular disorders | 2021 | PMID: 33673806 |
| Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients. | Alimohamed MZ | International journal of cardiology | 2021 | PMID: 33662488 |
| Hypertrophic cardiomyopathy associated E22K mutation in myosin regulatory light chain decreases calcium-activated tension and stiffness and reduces myofilament Ca(2+) sensitivity. | Zhang J | The FEBS journal | 2021 | PMID: 33548158 |
| Exome sequencing and characterization of 49,960 individuals in the UK Biobank. | Van Hout CV | Nature | 2020 | PMID: 33087929 |
| Implications of Genetic Testing in Dilated Cardiomyopathy. | Verdonschot JAJ | Circulation. Genomic and precision medicine | 2020 | PMID: 32880476 |
| Reduced penetrance of pathogenic ACMG variants in a deeply phenotyped cohort study and evaluation of ClinVar classification over time. | van Rooij J | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32665702 |
| Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy. | Robyns T | European journal of medical genetics | 2020 | PMID: 31513939 |
| Large next-generation sequencing gene panels in genetic heart disease: yield of pathogenic variants and variants of unknown significance. | van Lint FHM | Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation | 2019 | PMID: 30847666 |
| Hereditary heart disease: pathophysiology, clinical presentation, and animal models of HCM, RCM, and DCM associated with mutations in cardiac myosin light chains. | Yadav S | Pflugers Archiv : European journal of physiology | 2019 | PMID: 30706179 |
| Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy. | Mademont-Soler I | PloS one | 2017 | PMID: 28771489 |
| Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation. | Kobayashi Y | Genome medicine | 2017 | PMID: 28166811 |
| Usefulness of Genetic Testing in Hypertrophic Cardiomyopathy: an Analysis Using Real-World Data. | Alejandra Restrepo-Cordoba M | Journal of cardiovascular translational research | 2017 | PMID: 28138913 |
| 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 |
| Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young. | Methner DN | Genome research | 2016 | PMID: 27435932 |
| Hypertrophic remodelling in cardiac regulatory myosin light chain (MYL2) founder mutation carriers. | Claes GR | European heart journal | 2016 | PMID: 26497160 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. | Lopes LR | Heart (British Cardiac Society) | 2015 | PMID: 25351510 |
| Impact of familial hypertrophic cardiomyopathy-linked mutations in the NH2 terminus of the RLC on β-myosin cross-bridge mechanics. | Farman GP | Journal of applied physiology (Bethesda, Md. : 1985) | 2014 | PMID: 25324513 |
| Genetic basis of end-stage hypertrophic cardiomyopathy. | Garcia-Pavia P | European journal of heart failure | 2011 | PMID: 21896538 |
| Development and validation of a computational method for assessment of missense variants in hypertrophic cardiomyopathy. | Jordan DM | American journal of human genetics | 2011 | PMID: 21310275 |
| Myosin regulatory light chain E22K mutation results in decreased cardiac intracellular calcium and force transients. | Szczesna-Cordary D | FASEB journal : official publication of the Federation of American Societies for Experimental Biology | 2007 | PMID: 17606808 |
| E22K mutation of RLC that causes familial hypertrophic cardiomyopathy in heterozygous mouse myocardium: effect on cross-bridge kinetics. | Dumka D | American journal of physiology. Heart and circulatory physiology | 2006 | PMID: 16751284 |
| The E22K mutation of myosin RLC that causes familial hypertrophic cardiomyopathy increases calcium sensitivity of force and ATPase in transgenic mice. | Szczesna-Cordary D | Journal of cell science | 2005 | PMID: 16076902 |
| Familial hypertrophic cardiomyopathy-linked alterations in Ca2+ binding of human cardiac myosin regulatory light chain affect cardiac muscle contraction. | Szczesna-Cordary D | The Journal of biological chemistry | 2004 | PMID: 14594949 |
| Mechanical defects of muscle fibers with myosin light chain mutants that cause cardiomyopathy. | Roopnarine O | Biophysical journal | 2003 | PMID: 12668451 |
| Systematic analysis of the regulatory and essential myosin light chain genes: genetic variants and mutations in hypertrophic cardiomyopathy. | Kabaeva ZT | European journal of human genetics : EJHG | 2002 | PMID: 12404107 |
| Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding, and phosphorylation. | Szczesna D | The Journal of biological chemistry | 2001 | PMID: 11102452 |
| In vivo analysis of an essential myosin light chain mutation linked to familial hypertrophic cardiomyopathy. | Sanbe A | Circulation research | 2000 | PMID: 10948063 |
| Structural and functional responses of mammalian thick filaments to alterations in myosin regulatory light chains. | Levine RJ | Journal of structural biology | 1998 | PMID: 9724616 |
| Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle. | Poetter K | Nature genetics | 1996 | PMID: 8673105 |
| Role of cyclic GMP in the action of heat-stable enterotoxin of Escherichia coli. | Hughes JM | Nature | 1978 | PMID: 203862 |
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Record last updated Nov 19, 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.