chr14-23431768-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_000257.4(MYH7):c.632C>T(p.Pro211Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000223 in 1,614,118 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152240Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251490Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135918
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461878Hom.: 1 Cov.: 34 AF XY: 0.0000248 AC XY: 18AN XY: 727236
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74376
ClinVar
Submissions by phenotype
not provided Uncertain:4
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MYH7: PM2, BP4 -
Identified in patients with HCM in published literature, including one apparently homozygous observation; at least one patient harbored additional cardiogenetic variants (PMID: 37652022, 37466024, 38158977, 12820698, 12975413, 15856146, 21511876, 27532257); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18761664, 12975413, 15856146, 12820698, 21511876, 28420666, 34426522, 34542152, 27532257, 29300372, 37652022, 37466024, 38158977) -
Cardiomyopathy Uncertain:2
This missense variant replaces proline with leucine at codon 211 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 12820698, 12975413, 15856146, 18761664, 21511876). Two of these individuals carried a pathogenic mutation in the same gene (PMID: 12820698, 18761664). This variant has been identified in 4/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
This missense variant replaces proline with leucine at codon 211 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 12820698, 12975413, 15856146, 18761664, 21511876). Two of these individuals carried a pathogenic mutation in the same gene (PMID: 12820698, 18761664). This variant has been identified in 4/251490 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Hypertrophic cardiomyopathy Uncertain:2
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 211 of the MYH7 protein (p.Pro211Leu). This variant is present in population databases (rs727503277, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12820698, 12975413, 15856146, 18761664, 21511876, 27532257, 37466024, 38002985). ClinVar contains an entry for this variant (Variation ID: 164395). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYH7 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
The p.Pro211Leu variant in MYH7 has been identified in at least 5 individuals with HCM, and has additionally been identified in one individual who carried an additional pathogenic variant in MYH7 (Mohiddin 2003, Woo 2003, Perrot 2005, Gruner 2011, Kassem 2017, Walsh 2017, LMM data). However, the individual with a second pathogenic did not have early onset of disease, and while one affected relative had both variants, a second affected relative only had the second variant in MYH7. The p.Pro211Leu variant has also been identified in 4/251490 of chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational tools suggest that this p.Pro211Leu may not impact the protein; however, this variant lies in the head region of the protein and missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2017). In summary, although the data suggests an association with disease, the clinical significance of the p.Pro211Leu variant is uncertain. ACMG/AMP criteria applied: PM1, PM2, PS4_Supporting, BP4. -
Primary familial hypertrophic cardiomyopathy Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.P211L variant (also known as c.632C>T), located in coding exon 5 of the MYH7 gene, results from a C to T substitution at nucleotide position 632. The proline at codon 211 is replaced by leucine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This variant has been detected in individuals with hypertrophic cardiomyopathy (HCM) or from HCM cohorts; however, some individuals also had additional variants detected, or gene analysis was limited (Woo A et al. Heart, 2003 Oct;89:1179-85; Mohiddin SA et al. Genet Test, 2003;7:21-7; Perrot A et al. J Mol Med (Berl), 2005 Jun;83:468-77; Gruner C et al. Circ Cardiovasc Genet, 2011 Jun;4:288-95; Walsh R et al. Genet Med, 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Hypertrophic cardiomyopathy 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at