14-23425345-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. BS1BP2PM1
This summary comes from the ClinGen Evidence Repository: The c.2360G>A (p.Arg787His) variant in MYH7 has been identified in 0.10% (FAF 95% CI; 41/30616) of South Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID:29300386). Additionally, while 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; Walsh 2017 PMID:27532257), this pathogenic evidence code (PM1) was not considered to be in conflict with a likely benign conclusion. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1, PM1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA012239/MONDO:0005045/002
Frequency
Consequence
NM_000257.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000789 AC: 12AN: 152120Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000199 AC: 50AN: 251472Hom.: 0 AF XY: 0.000265 AC XY: 36AN XY: 135912
GnomAD4 exome AF: 0.000179 AC: 262AN: 1461890Hom.: 1 Cov.: 33 AF XY: 0.000232 AC XY: 169AN XY: 727246
GnomAD4 genome 0.0000788 AC: 12AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74430
ClinVar
Submissions by phenotype
not specified Uncertain:5
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The Arg787His variant has been reported in 7 probands (6 with HCM and 1 with DCM ), has been detected by our laboratory in 4 additional individuals with HCM. The majority of these individuals were of Indian or Arabic descent (Richard 2003, Y u 2005, Laredo 2006, Boda 2009, Rai 2009, Purushotham 2010; LMM unpublished data ). Three of 11 probands (2: LMM, 1: Laredo 2006) carried a second variant suffi cient to explain their disease. The variant was present in 1/4406 African Americ an chromosomes from a broad population screened by the NHLBI Exome Sequencing pr oject (http://evs.gs.washington.edu/EVS) but absent from 600 were race-matched c hromosomes (Purushotham 2010) and 600 additional chromosomes across several stud ies (Richard 2003, Yu 2005, Laredo 2006, Boda 2009, Rai 2009). Another variant a t the same position (Arg787Cys) has been reported in individuals with HCM (Morit a 2008, Garcia-Castro 2009); however, the affected amino acid (arginine) is only moderately conserved in evolution, suggesting that a change may be tolerated or be milder. A milder effect was also suspected by Purushotham 2010 who detected the variant in 2 affected individuals but also 8 asymptomatic relatives. Of not e, one of these families had a history of sudden death including the son of an i ndividual who tested negative for the Arg787His variant. While a phenocopy cann ot be ruled out this possible non-segregation raises concern regarding the patho genicity of the Arg787His variant. In summary, the data for this variant is some what conflicting and additional studies are needed to clarify its role in diseas e. -
Variant summary: MYH7 c.2360G>A (p.Arg787His) results in a non-conservative amino acid change located in the Myosin head, motor domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251472 control chromosomes, predominantly at a frequency of 0.0013 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.039 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH7 causing Cardiomyopathy phenotype (0.0013), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.2360G>A has been reported in the literature in multiple individuals affected with Cardiomyopathy. However, the variant has also been observed in multiple families that showed lack of cosegregation with disease including unaffected individuals with the variant and affected individuals without the variant (Purushotham_2010, Laredo_2006). In addition, the variant has been observed to co-occur with other pathogenic variants, MYBPC3 c.3641G>A, p.W1214X; MYH7, I736T), providing supporting evidence for a benign role. A functional study, Sequeira_2013, indicates the variant to have higher Ca 2+ sensitivity and low phosphorylation of protein kinase A targets compared to donors, along with length-dependent activation being significantly smaller. Ten ClinVar submissions (evaluation after 2014) cite the variant five times as likely benign, while five other submissions including the expert panel, ClinGen, cite the variant as uncertain signfiicance. In addition, another variant affecting the same codon, R787C, has been reported in affected individuals suggesting the location could be important for protein function. Based on the evidence outlined above, the variant was classified as uncertain significance. -
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. MYH7 p.Arg787His We consider this a variant of uncertain significance, likely disease causing, based on the co-occurrence of another pathogenic variant in several of the cases with multi-gene sequencing and the possible failure to segregate in one family. The variant has been seen in at least 9 unrelated cases of cardiomyopathy (not including the patient). Three patients had another variant sufficient to explain their disease. Five of the other cases had insufficient sequencing to determine if another variant was present. There is weak segregation data in two families, though in one of them there is potential for failure to segregate with insufficient information available. Richard P et al., 2003 first described this variant in a European individual with HCM. They sequenced 9 genes (MYH7, MYBPC3, TNNI3, TNNT2, MYL2, MYL3, TPM1, ACTC and TNNC1) in 197 unrelated index cases with HCM. Patients were recruited from France and most of them were of European origin. No details regarding this patient's phenotype was given. Yu et al (2005) observed the variant in one of 150 patients with HCM from their Australian cohort. They reported only on analysis of MYH7. Laredo et al (2006) reported this variant in a 43 year old Spanish female, who also harbored p.Ile736Thr variant in the MYH7 gene (which we classify as likely disease causing). They sequenced MYH7 in 128 patients with HCM to compare the phenotypes of those with and without mutations in MYH7. The patient who harbored this variant in addition to the p.Ile736Thr variant in MYH7 was a female diagnosed at age 43 with a maximum thickness of 30mm and asymmetric hypertrophic morphology. The patient's mother was diagnosed with HCM at age 43 and had undergone a myectomy and died from heart failure at age 69. It appears that the father tested negative for both variants. The patient's sons both inherited only the p.Ile736Thr variant, revealing that these variants were in trans. Her eldest son had some hypertrophy with maximal thickness of 11mm at age 21. Her youngest son had maximal thickness of 13mm with asymmetric hypertrophy at age 16. None of the studied family members had just p.Arg787His. Boda et al (2009) observed the variant in one of 100 idiopathic DCM cases in their Indian cohort. They analyzed MYH7, TNNI3, ACTC. Rai et al (2009) observed the variant in one of 69 patients with HCM in their Indian cohort. They only analyzed MYH7. Purushotham et al. (2010) reported this variant in two unrelated Indian patients with HCM. The authors sequenced exons 3-23 of the MYH7 gene and all exons of the MYBPC3 gene. The authors did not sequence other genes in the patients identified to carry the p.Arg787His variant. In each family there were two affected first degree relatives who carry the variant. Of note, in one of these families there was an "uninvestigated sudden death" in the child of someone who tested negative for the variant, suggesting a possible failure to segregate. This variant is located in exon 21 of the MYH7 gene. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging. The arginine at codon 787 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at this codon (p.Arg787Cys) and nearby codons (Ser782Asn; Arg783His, Arg793Gln). Purushotham and colleagues presented some functional data which suggested that this substitution is not tolerated. Sequence and structure analysis of the MYH7 mutation revealed that the mutant protein might be compromised in its ability to bind essential light chain efficiently. The authors suggested that the MYH7 p.Arg787His variant may resu -
not provided Uncertain:2Benign:2
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This variant is associated with the following publications: (PMID: 17125710, 29343710, 20086309, 12707239, 31006259, 20664766, 20433692, 21959974, 22957257, 23299917, 25228707, 25637381, 27247418, 28518168, 30731207, 29300372, 30847666, 31638223) -
Hypertrophic cardiomyopathy 1 Benign:3
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The MYH7 Arg787His variant occurs in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.02%. In silico tools (SIFT, PolyPhen-HCM, MutationTaster) are in support of a benign role. The MHY7 Arg787His variant was identified in a HCM proband with no family history of disease. The proband also harbours 2 additional MYBPC3 variants (p.Ala693Val & p.Arg817Gly) that are likely contributing to the disease phenotype. A second individual with non-diagnostic hypertrophy was also identified with this variant. Based on the high frequency in the general population and in silico tool predicting a benign effect, we classify MYH7 Arg787His as "likely benign". -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Primary familial hypertrophic cardiomyopathy Uncertain:2
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Cardiomyopathy Benign:2
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Hypertrophic cardiomyopathy Benign:2
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The c.2360G>A (p.Arg787His) variant in MYH7 has been identified in 0.10% (FAF 95% CI; 41/30616) of South Asian chromosomes in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen Inherited Cardiomyopathy Expert Panel (BS1; Kelly 2018 PMID:29300372). Allowing a variant to reach a likely benign classification based on BS1 alone represents a revision of the original ACMG/AMP framework by ClinGen’s Sequence Variant Interpretation Working Group (Tavtigian 2018 PMID: 29300386). Additionally, while 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; Walsh 2017 PMID:27532257), this pathogenic evidence code (PM1) was not considered to be in conflict with a likely benign conclusion. In summary, this variant meets criteria to be classified as likely benign for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): BS1, PM1. -
Dilated cardiomyopathy 1S Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
MYH7-related skeletal myopathy Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Myosin storage myopathy Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Left ventricular noncompaction cardiomyopathy Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at