14-23425980-C-T
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS4PP1_StrongPP3PM6PM1PM2
This summary comes from the ClinGen Evidence Repository: The c.2146G>A (p.Gly716Arg) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (PS4; PMID:23074333; PMID:20641121; PMID:12084606; PMID:8282798; PMID:18953637; PMID:12707239; PMID:15358028; PMID:12975413; Partners LMM ClinVar SCV000059418.5; SHaRe consortium, PMID:30297972). This variant has been identified as a de novo occurrence in 2 probands with hypertrophic cardiomyopathy (PM6; PMID:18953637; Partners LMM ClinVar SCV000059418.5). This variant segregated with disease in 11 affected individuals (PP1_Strong; PMID:8282798; PMID:20641121; Partners LMM ClinVar SCV000059418.5). 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). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). 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; PP1_ Strong; PM1; PM2; PM6; PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA011770/MONDO:0005045/002
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 33
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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.Gly716Arg in the MYH7 gene. The variant has been seen in at least 10 unrelated cases of HCM, with strong segregation data. The variant was first reported by the Seidman group in three affected first degree relatives (Anan et al 1994). Hwang et al (1998) then reported a Korean family with 5 individuals with HCM who all had the variant (two were fourth degree relatives to each other). The same group later reported longterm follow-up on that family noting that all 15 family members with HCM carried the p.Gly716Arg variant. Ackerman et al (2002) reported a patient with HCM and p.Gly716Arg who had a quite significant family history, though unfortunately no genotyping on family members was reported. This is likely the same case that was later reported in van Driest et al 2004. Richard et al (2003) observed the variant in two unrelated individuals with HCM is their French cohort. Woo et al (2003) reported two individuals with HCM and this variant in their Canadian cohort. Millat et al (2010) reported one HCM patient with p.Gly716Arg in their French cohort, which seems to be distinct from the Richard et al cohort. Rai et al (2009) reported this variant arising de novo in a proband with severe hypertrophy who died suddenly. Parental genotypes and paternity were molecularly confirmed. Parents and a brother were reported as phenotypically normal (though it is unclear if they had cardiac evaluations). Most of the reported families had a particularly high penetrance with severe disease. This variant has also been reported in one individual in our center with HCM and a strong family history of HCM and RCM with multiple family members requiring transplant. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The glycine at codon 716 is conserved across species, as are neighboring amino acids. No other variants have been reported in association with disease at this codon. Variants at nearby codons have been reported in association with HCM (p.Arg712Leu, p.Arg719Trp, p.Arg719Gln, p.Arg719Pro, p.Arg723Cys, p.Arg723Gly). In total the variant has not been seen in ~6,900 published controls and publicly available population datasets. There is no variation at codon 716 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 2/6/14). Please note, this does not match the patient's ancestry (Hispanic). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 2/6/14). The variant was not observed in the following published control samples: more than 100 individuals (Anan et al 1994), 100 (Richard et al 2003), 200 (van Driest et al 2004). -
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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; Published functional studies demonstrate a damaging effect as the p.(G716R) variant exhibited weak affinity with actin and generated a low level of force (Fujita et al., 1997); Reported as pathogenic in ClinVar by the ClinGen Cardiomyopathy Variant Curation Expert Panel; This variant is associated with the following publications: (PMID: 24033266, 15358028, 8282798, 9874056, 25935763, 24093860, 12084606, 12975413, 27161882, 28166811, 27532257, 27247418, 21310275, 18953637, 12707239, 20641121, 29300372, 30165862, 29907873, 29696744, 23074333, 20624503, 23283745, 20031618, 31912959, 32894683, 9062359, 27535533, 26582918) -
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Hypertrophic cardiomyopathy 1 Pathogenic:4
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 glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 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 in the myosin head motor domain which has very little benign variation (Decipher, PMID: 29300372). (SP) 0708 - Other missense variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. The p.(Gly716Glu) variant has been classified as a VUS by clinical diagnostic laboratories while the p.(Gly716Ala) variant has been identified in an Egyptian study of HCM and classified as likely pathogenic (ClinVar, PMID: 23233322). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as Pathogenic by the Clingen expert panel (ClinVar). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been demonstrated to segregate in seven individuals across two families (PMIDs: 20641121, 8282798, 29300372). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant D. discoideum cells carrying the D. discoideum equivalent of p.(Gly716Arg) demonstrated increased actin-activated ATPase activity, weak affinity with actin, reduced force and sliding velocity of actin filaments compared to WT cells (PMID: 9062359). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
MYH7 Gly716Arg has been previously reported in at least 15 HCM probands (Walsh R, et al., 2017; Garcia-Giustiniani D, et al., 2015; Marsiglia JD, et al., 2013; Zheng DD, et al., 2010; Rai TS, et al., 2009; Richard P, et al., 2003; Woo A, et al., 2003; Ackerman MJ, et al., 2002; Hwang TH, et al., 1998; Anan R, et al., 1994), including 2 de novo case (Zheng DD, et al., 2010; Rai TS, et al., 2009). It has also been reported to segregate in multiple affected individuals in several families (Garcia-Giustiniani D, et al., 2015; Hwang TH, et al., 1998; Choi Anan R, et al., 1994). We have identified this variant 2 probands diagnosed with HCM. In one family the variant segregated to an affected first-degree family member. The variant is very rare, being absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools PolyPhen2, CADD and MutationTaster predict this variant to be deleterious, however SIFT predicts this variant to be 'tolerated'. Functional studies suggest that the Gly716Arg variant decreases the affinity of myosin II to actin, which results in reduced force generation and subsequently compensatory hypertrophy (Fujita et al., 1997). In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Furthermore variant located in the converter region of MYH7 are predicted to result in worse outcomes (Garcia-Giustiniani D, et al., 2015). Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant has been reported in more than 10 unrelated probands (PS4), segregates strongly with disease (PP1_Strong), is located in a mutational hotspot (PM1), is rare in the general population (PM2) and has been reported in de novo cases (PM5) therefore we classify MYH7 Gly716Arg as 'Pathogenic'. -
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Hypertrophic cardiomyopathy Pathogenic:3
The c.2146G>A (p.Gly716Arg) variant in MYH7 has been reported in >30 individuals with hypertrophic cardiomyopathy (PS4; PMID:23074333; PMID:20641121; PMID:12084606; PMID:8282798; PMID:18953637; PMID:12707239; PMID:15358028; PMID:12975413; Partners LMM ClinVar SCV000059418.5; SHaRe consortium, PMID: 30297972). This variant has been identified as a de novo occurrence in 2 probands with hypertrophic cardiomyopathy (PM6; PMID:18953637; Partners LMM ClinVar SCV000059418.5). This variant segregated with disease in 11 affected individuals (PP1_Strong; PMID:8282798; PMID:20641121; Partners LMM ClinVar SCV000059418.5). 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). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). 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; PP1_ Strong; PM1; PM2; PM6; PP3 -
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 716 of the MYH7 protein (p.Gly716Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) (PMID: 8282798, 9874056, 12084606, 12707239, 12975413, 18953637, 20031618, 20624503, 23283745, 24093860, 25935763, 27161882). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14105). 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 have shown that this missense change affects MYH7 function (PMID: 9062359). For these reasons, this variant has been classified as Pathogenic. -
proposed classification - variant undergoing re-assessment, contact laboratory -
Cardiomyopathy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at