chr14-23425774-A-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP1_ModeratePS4PM1PM2
This summary comes from the ClinGen Evidence Repository: The c.2207T>C (p.Ile736Thr) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:16630449; PMID:12974739; PMID:16199542; PMID:15856146; PMID:17125710; PMID:20738943; SHaRe consortium, PMID:30297972; Partners LMM ClinVar SCV000199207.4; AGCMC Sydney ClinVar SCV000212631.2). This variant segregated with disease in 5 affected individuals (PP1_Moderate; PMID:15856146; PMID:17125710; Partners LMM ClinVar SCV000199207.4). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP1_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA011970/MONDO:0005045/002
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 33
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 1 Pathogenic:5
- -
This MYH7 Ile736Thr variant has been identified in multiple unrelated HCM individuals (see literature) and has been found to segregate in at least 2 families (Perrot A, et al., 2005; Laredo R, et al., 2007). The Ile736Thr variant occurs in the converter domain of the MYH7 which is generally associated with poorer outcomes in cardiomyopathy patients, however patients carrying this specific mutation were found to have less adverse events (GarcÃa-Giustiniani D, et al., 2015). We have identified this variant in two HCM index cases in our patient cohort. The variant is absent from the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational tools SIFT, PolyPhen-2 and MutationTaster predict the variant to be deleterious, however PolyPhen-HCM predicts this variant to be "benign". Based on multiple reports of the variant in HCM cases, strong segregation with disease, rarity in the general population and because missense MYH7 variants are a common cause of disease and rarely benign, we classify MYH7 Ile736Thr as "pathogenic". -
- -
The c.2207T>C (p.Ile736Thr) variant of MYH7 gene results in an amino acid change at residue 736 from an isoleucine to a threonine. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy (PMID: 16199542, 22112859, 23711808, 12820698, 12974739, 22455086, 27247418; 27532257). This variant segregated with disease in affected individuals (PMID: 15856146, 25935763, 17125710). This change is predicted to be deleterious by multiple in-silico algorithms and has not been observed in the gnomAD population variant database. Furthermore, this variant lies in a functionally important domain where other cardiomyopathy-associated missense variants have been described (PMID: 27532257). For these reasons, this variant c.2207T>C (p.Ile736Thr) variant in MYH7 is interpreted as pathogenic. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, however, missense variants have been proposed to act in a dominant negative manner (PMID: 24714796). (I) 0108 - This gene is associated with both recessive and dominant disease. Pathogenic variants in this gene are usually heterozygous, however a recessive inheritance pattern has been observed in severe cases (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 29300372). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (5 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. This variant is located within the myosin head domain, which is regarded as a missense variant hotspot (Decipher, PMID: 29300372). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with hypertrophic cardiomyopathy. This variant has been reported many times as pathogenic, including by an expert panel (ClinVar, cardiodb, PMID: 15856146). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:4
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. Ile736Thr (c.2207 T>C) in the MYH7 gene. The patient's genetic test results were last reviewed in September 2011. They were re-reviewed April 17th, 2013. There was no new case data on the variant, however there was new data on its prevalence in the general population. This variant has been reported in at least 9 unrelated cases with HCM (not including the patient) with weak segregation data (Mohiddin et al 2003; Perrot et al 2005; Ingles et al 2005; Liu et al 2006). Perrot et al (2005) reported the variant in three family members with HCM. Laredo et al (2006) reported the variant in three unrelated families with HCM; in one family the variant was observed in three affected individuals. We have seen the variant in another family with HCM. Other variants at the same codon have been reported in association with HCM: p.Ile736Val (Gorham et al 2003) and p.Ile736Met (Koyangi et al 1996, Muraishi et al 1999). Krischner et al (2005) reported the p.Ile736Thr is associated with a slightly increased calcium sensitivity and higher active forces at lower calcium concentrations with residual active force under relaxing conditions. PolyPhen-2 predicts the variant to be probably damaging (with a score of 1.00). The isoleucine at codon 736 is completely conserved across species and neighboring amino acids are either completely or highly conserved. In total the variant has not been seen in ~6996 published controls and individuals from publicly available population datasets. There is no variation at codon 736 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of April 17th, 2013). There is also no variation at this codon listed in dbSNP (as of April 17th, 2013). There is a variant at codon 736 listed in 1000 genomes, however that points to an HGMD entry (April 17th, 2013). The variant was not observed in the following published control samples: The p.Ile736Thr variant has been reported as absent in 96 (Perrot et al 2005), 100 (Mohiddin et al 2003), 100 (Laredo et al 2006), 150 (Ingles et al 2005), and 50 (Erdmann et al 2003) individuals for a total of 496 presumed healthy individuals. -
Not observed at significant frequency in large population cohorts (gnomAD); 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: 22112859, 8533830, 12974739, 19651039, 27247418, 28606303, 27532257, 15856146, 16199542, 23711808, 12820698, 17125710, 22455086, 25935763, 25346696, 26743238, 27217341, 21943931, 21472310, 21769673, 29398688, 29300372, 16630449, 19808356, 20738943, 20800588, 30775854, 31960626, 23074333, 29961767, 31513939, 33673806, 32894683, 33906374, 34542152, 35352813, 35626289, 35208637) -
- -
- -
Hypertrophic cardiomyopathy Pathogenic:4
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 736 of the MYH7 protein (p.Ile736Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12820698, 12974739, 15856146, 16199542, 22112859, 22455086, 23711808, 25935763). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164342). 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 expected to disrupt MYH7 protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MYH7 function (PMID: 19651039, 25346696). For these reasons, this variant has been classified as Pathogenic. -
The c.2207T>C (p.Ile736Thr) variant in MYH7 has been reported in >20 individuals with hypertrophic cardiomyopathy (PS4; PMID:16630449; PMID:12974739; PMID:16199542; PMID:15856146; PMID:17125710; PMID:20738943; SHaRe consortium, PMID: 30297972; Partners LMM ClinVar SCV000199207.4; AGCMC Sydney ClinVar SCV000212631.2). This variant segregated with disease in 5 affected individuals (PP1_Moderate; PMID:15856146; PMID:17125710; Partners LMM ClinVar SCV000199207.4). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP1_Moderate -
- -
The p.Ile736Thr variant in MYH7 has been reported in >10 individuals with HCM, segregated with disease in 7 affected relatives from 3 families (Erdman 2003 PMID: 12974739, Ingles 2005 PMID: 16199542, Liu 2006 PMID: 16630449, Laredo 2006 PMID: 17125710, Barriales Villa 2010 PMID: 20738943, LMM data), and was absent from large population studies. The variant has been reported in ClinVar (Variation ID 164342). In vitro functional studies provide some evidence that the p.Ile736Thr variant may not impact protein function (Seebohm 2009 PMID: 19651039, Tripathi 2011 PMID: 21769673). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, this variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon segregation studies and absence from controls. ACMG/AMP criteria applied: PS4, PP1_Strong, PM2_Supporting. -
Dilated cardiomyopathy 1S Pathogenic:1
- -
Cardiomyopathy Pathogenic:1
- -
Cardiovascular phenotype Pathogenic:1
The p.I736T pathogenic mutation (also known as c.2207T>C), located in coding exon 18 of the MYH7 gene, results from a T to C substitution at nucleotide position 2207. The isoleucine at codon 736 is replaced by threonine, an amino acid with similar properties. This amino acid position is located within the converter domain of cardiac b-myosin, which is enriched in HCM-associated pathogenic variants (Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6). This variant has been detected in multiple unrelated individuals with hypertrophic cardiomyopathy (Erdmann J et al. Clin. Genet., 2003 Oct;64:339-49; Mohiddin SA et al. Genet. Test., 2003;7:21-7; Perrot A et al. J. Mol. Med., 2005 Jun;83:468-77; Ingles J et al. J. Med. Genet., 2005 Oct;42:e59; Liu WL et al. Zhonghua Xin Xue Guan Bing Za Zhi, 2006 Mar;34:202-7; Laredo R et al. Rev Esp Cardiol, 2006 Oct;59:1008-18; García-Giustiniani D et al. Heart, 2015 Jul;101:1047-53; Curila K et al. Acta Cardiol, 2012 Feb;67:23-9; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). This variant has also been reported to segregate with HCM in families (Perrot A et al. J. Mol. Med., 2005 Jun;83:468-77; Liu WL et al. Zhonghua Xin Xue Guan Bing Za Zhi, 2006 Mar;34:202-7; Laredo R et al. Rev Esp Cardiol, 2006 Oct;59:1008-18). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this variant is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at