chr14-23424846-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS4_ModeratePM2PM1PP3
This summary comes from the ClinGen Evidence Repository: The NM_000257.4(MYH7):c.2602G>C (p.Ala868Pro) variant has been identified in at least 13 probands with HCM (PM4_Moderate; Millat 2010 PMID:20624503; Millat 2010 PMID:20800588; Walsh 2017 PMID:27532257; Ambry pers. comm., GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers. comm.). Additionally, this variant was reported in a patient with suspected RCM/HCM as well as arrhythmia, who also carried the pathogenic NM_000257.4(MYH7):c.2167C>T p.(Arg723Cys) variant. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.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 associated with HCM (PM1; Walsh 2017 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 likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM4_Moderate, PM2, PM1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA012698/MONDO:0005045/002
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461890Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 genome
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:4
The NM_000257.4(MYH7):c.2602G>C (p.Ala868Pro) variant has been identified in at least 13 probands with HCM (PM4_Moderate; Millat 2010 PMID:20624503; Millat 2010 PMID:20800588; Walsh 2017 PMID: 27532257; Ambry pers. comm., GeneDx pers. comm., Invitae pers. comm., LMM pers. comm., OMGL pers. comm.). Additionally, this variant was reported in a patient with suspected RCM/HCM as well as arrhythmia, who also carried the pathogenic NM_000257.4(MYH7):c.2167C>T p.(Arg723Cys) variant. This variant was absent from large population studies (PM2; gnomAD v2.1.1, http://gnomad.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 associated with HCM (PM1; Walsh 2017 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 likely pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM4_Moderate, PM2, PM1, PP3. -
This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 868 of the MYH7 protein (p.Ala868Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 2062450, 27532257; internal data). ClinVar contains an entry for this variant (Variation ID: 177847). 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%. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic. -
The p.Ala868Pro variant in MYH7 has been reported in at least 8 individuals with HCM (Millat 2010, Walsh 2017, LMM data, Invitae personal communication, ClinVar Variation ID 177847), including 1 individual with early-onset HCM who also carried a pathogenic variant in the MYBPC3 gene. It has also been reported to segregate with HCM in one affected family member (ClinVar submission SCV000924872.1). This variant was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. However, this variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PM1, PM2, PS4_Moderate. -
This missense variant replaces alanine with proline at codon 868 in the myosin head/motor domain of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in eight unrelated individuals affected with hypertrophic cardiomyopathy (MID: 20624503, 27532257, 33495597; communication with external laboratories, ClinVar variation ID: 177847). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
not provided Pathogenic:2Uncertain:1
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; Reported in ClinVar as a likely pathogenic variant by the ClinGen Cardiomyopathy Variant Curation Expert Panel; This variant is associated with the following publications: (PMID: 27532257, 21310275, 17095604, 2062450, 20800588, 20624503, 29300372, 37652022, 34680864, 38716318, 34714385, 27247418) -
This patient has a diagnosis of HCM and had a Comprehensive Cardiomyopathy Panel with the GeneDx laboratory. The test included sequencing of 76 genes and additional deletion/duplication analysis of 60 of those genes (nuclear genes) associated with various forms of cardiomyopathy: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3 , BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL , NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. 7 variants were reported. We believe the MYH7 variant is the most likely to be pathogenic: • p.Ala868Pro (A868P; c.2602G>C) in the MYH7 gene • p.Leu327Val (L327V; c.979C>G) in the PRKAG2 gene • p.Pro323Thr (P323T; c.967C>A) in the GLA gene • p.Ala749Ile (A749I; c.2245_2246delGCinsAT) in the PKP2 gene • p.Met89Thr (M89T; c.266T>C) in the JUP gene • p.Asp2771Ala (D2771A; c.8312A>C) in the DMD gene • Duplication of at least exons 1-2 of the LAMA4 gene Given the large number of genes included on this panel, and the large and variable nature of some of these genes, it is expected that most individuals (including individuals who don't have inherited cardiac disease) would have at least one and possibly several rare variants found with this test. As a result, it is important to consider the data available on each variant to determine whether it is a disease-predisposing variant or one of the many benign rare variants that we all have in our DNA. p.Ala868Pro (A868P; c.2602G>C) in exon 22 of the MYH7 gene (NM_000257.2) Chromosome position: 14:23894055 C / G Based on the information reviewed below, including the presence in cases with HCM, the absence in general population controls, and the likely structural disruption this variant would cause to the protein, we classify it as a Variant of Uncertain Significance (VUS)-probably disease causing, concluding that it is highly suspicious but that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing in at-risk relatives at this time. The Laboratory for Molecular Medicine and Invitae have both submitted it to ClinVar as a VUS. This variant has previously been reported in at least 3 individuals with a stated diagnosis of HCM. Alfares et al. from the Laboratory for Molecular Medicine reported it in 2015 in one person tested for HCM at their laboratory. Millat et al. (2010) reported it in 2 unrelated French probands clinically diagnosed with HCM. However, one of these individuals (diagnosed at one year of age) also had a missense variant in the MYBPC3 gene: p.Arg1022Pro (Millat et al. 2010). There is no published segregation data for Ala868Pro. However, in our patient’s family the variant does segregate with disease in this patient and her daughter who have both been clinically diagnosed with HCM. This is a conservative amino acid change, resulting in the replacement of a nonpolar Alanine with a nonpolar Proline. However, this residue falls within the S2 subfragment of myosin (residues 848-1216; Colegrave and Peckham 2014), which is a highly repetitive amino acid sequence at the beginning of the rod domain that forms an alpha-helical coiled-coil structure. Proline is known to break alpha helices, and it could therefore disrupt the structure of this protein domain or disrupt the higher-order formation of sarcomere thick filaments. Alanine at this location is highly conserved across vertebrate species. The surrounding residues are also highly conserved. Nearby residue p.Arg870His is considered solidly Pathogenic by multiple submitters to ClinVar. In silico analysis with PolyPhen-2 predicts the Ala868Pro variant to be “Possibly Damaging†-
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Cardiomyopathy Pathogenic:1
This missense variant replaces alanine with proline at codon 868 in the myosin head/motor domain of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 10 unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 27532257, 33495597; communication with external laboratories: ClinVar Variation ID: 177847). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Primary familial hypertrophic cardiomyopathy Pathogenic:1
Variant summary: MYH7 c.2602G>C (p.Ala868Pro) results in a non-conservative amino acid change located in the Myosin tail (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251458 control chromosomes. c.2602G>C has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (Millat_2010, Walsh_2017, Gal_2022, Holler_2021, McGurk_2023, Silva_2024). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34714385, 34680864, 37652022, 20624503, 38716318, 27532257). ClinVar contains an entry for this variant (Variation ID: 177847). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Cardiovascular phenotype Pathogenic:1
The p.A868P variant (also known as c.2602G>C), located in coding exon 20 of the MYH7 gene, results from a G to C substitution at nucleotide position 2602. The alanine at codon 868 is replaced by proline, an amino acid with highly 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 was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) (Millat G et al. Eur J Med Genet, 2010 Jul;53:261-7; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Hypertrophic cardiomyopathy 1 Pathogenic:1
The MYH7 c.2602G>C (p.Ala868Pro) missense variant has been reported in at least four individuals with hypertrophic cardiomyopathy, one of whom also had a variant in the MYBPC3 gene (PMID: 27532257; 20624503). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. It is located in the head region of the protein, where missense variants are statistically more likely to be associated with hypertrophic cardiomyopathy (PMID: 27532257). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. This variant has been classified as likely pathogenic by the ClinGen Cardiomyopathy Variant Curation Expert Panel and multiple other submitters in ClinVar. Based on the available evidence, the c.2602G>C (p.Ala868Pro) variant is classified as likely pathogenic for hypertrophic cardiomyopathy. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at