ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2389G>A (p.Ala797Thr) (rs3218716)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000473164 SCV000059441 pathogenic Hypertrophic cardiomyopathy 2021-03-04 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
CSER _CC_NCGL, University of Washington RCV000035790 SCV000190422 likely pathogenic Primary familial hypertrophic cardiomyopathy 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000158532 SCV000208467 pathogenic not provided 2021-08-27 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29300372, 27532257, 26582918, 33297573, 30755392, 33673806, 31589614, 31447099, 30291343, 32233023, 32420109, 31006259, 11186938, 16858239, 19880069, 20031618, 22857948, 23283745, 23782526, 24111713, 25351510, 25937619, 28408708, 29687901, 28615295, 28420666, 28790153, 21310275, 28606303, 28971120, 28138913, 27831900, 27247418, 24793961, 26969327, 27737317, 28166811, 24093860, 19287818, 10521296, 15358028, 23233322, 7581410, 25031304, 23299917, 25637381, 18029407, 17125710, 29260236, 26743238)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000158532 SCV000227613 pathogenic not provided 2015-01-30 criteria provided, single submitter clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000168872 SCV000256118 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000473164 SCV000256638 pathogenic Hypertrophic cardiomyopathy 2018-06-14 criteria provided, single submitter research MYH7 Ala797Thr has previously been described in HCM patients from at least 11 centres (Moolman., et al 1995; Van Driest., et al 2004; Laredo., et al 2007; Revera., et al 2008; Kaski., et al 2009; Brito., et al 2012; Marsiglia., et al 2013; Kassem., et al 2013; Berge & Leren., et al 2014; Walsh., et al 2017). Strong co-segregation of this variant with disease has been demonstrated in unrelated families (Moolman., et al 1995; Laredo., et al 2007). The variant is present in the Exome Aggregation Consortium dataset (MAF=0.00003; Moolman et al first identified this variant (1995) and haplotype analysis in subsequent papers led them to suggest it may be a South African founder variant (2000). We have observed the Ala797Thr variant in three unrelated HCM probands, one of these proband also has a second MYH7 variant (p.Arg807His) which was inherited in trans. 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. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant has been reported in well over 15 HCM probands (PS4), segregates with disease in multiple families (PP1_strong), is located in a known functional domain of MYH7 (PM1) and is rare in the general population (PM2), therefore we classify MYH7 Ala797Thr as "pathogenic".
Invitae RCV000473164 SCV000546240 pathogenic Hypertrophic cardiomyopathy 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 797 of the MYH7 protein (p.Ala797Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant has been reported to segregate with hypertrophic cardiomyopathy in several families (PMID: 10521296, 17125710). It has also been found in multiple unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 10521296, 23233322, 24111713, 19880069, 22857948, 23283745, 16858239, 24093860, 20031618). ClinVar contains an entry for this variant (Variation ID: 42901). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000515299 SCV000611216 pathogenic Familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; Myopathy, distal, 1; MYH7-related late-onset scapuloperoneal muscular dystrophy 2017-05-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620547 SCV000736226 pathogenic Cardiovascular phenotype 2018-08-04 criteria provided, single submitter clinical testing The p.A797T pathogenic mutation (also known as c.2389G>A), located in coding exon 19 of the MYH7 gene, results from a G to A substitution at nucleotide position 2389. The alanine at codon 797 is replaced by threonine, an amino acid with similar properties. This mutation has been reported in association with hypertrophic cardiomyopathy (HCM) and has shown a founder effect in the South African population (Moolman JC et al. Hum Mutat. 1995;6(2):197-8; Moolman-Smook JC et al. Am J Hum Genet. 1999;65(5):1308-20; Revera M et al. Cardiovasc Res. 2008;77(4):687-94; Brito D et al. Rev Port Cardiol. 2012;31(9):577-87; Kassem HSh et al. J Cardiovasc Transl Res. 2013;6(1):65-80; Lopes LR et al. Heart. 2015;01(4):294-301; Walsh R et al. Genet. Med. 2017;19(2):192-203). This alteration has also segregated with disease across several families (Moolman-Smook JC et al. Am J Hum Genet. 1999;65(5):1308-20; Moolman-Smook J et al. J Med Genet. 2000;37(12):951-6; Laredo R et al. Rev Esp Cardiol. 2006;59(10):1008-18). Based on the supporting evidence, p.A797T is interpreted as a disease-causing mutation.
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735308 SCV000854461 likely pathogenic Severe combined immunodeficiency disease; Immunodeficiency; Lymphopenia; Abnormality of cellular immune system; Abnormality of T cell physiology; Combined T and B cell immunodeficiency criteria provided, single submitter clinical testing
Blueprint Genetics RCV000158532 SCV000927576 pathogenic not provided 2018-03-07 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845386 SCV000987447 pathogenic Primary familial dilated cardiomyopathy criteria provided, single submitter clinical testing
Color Health, Inc RCV001189214 SCV001356459 likely pathogenic Cardiomyopathy 2019-02-20 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000158532 SCV000280322 pathogenic not provided 2014-07-23 no assertion criteria provided clinical testing 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.Ala797Thr (c.2389 G>A) in the MYH7 gene. We classify it as likely disease causing, based on the data reviewed below. The variant has been observed in 14 families with HCM thought to originate from the same founder and an additional 20 presumably unrelated patients with HCM. There is strong segregation data within the founder families and moderate segregation data in other cases. The variant was first published by Moolman-Smook et al in 1995. They reported one Caucasian South African family in which the variant segregated with cardiomyopathy in four first degree relatives. They subsequently identified the variant in several other families and reported that haplotype analysis was consistent with a founder effect (Moolman-Smook et al 2000). This same group published a review that notes that they have observed p.Ala797Thr in 14 families with 80 carriers of this variant (Bink et al 2009). In studying these kindreds the authors have observed that this variant is associated with age-dependent penetrance, with only 2/3 of carriers having hypertrophy by age 35. The variant was also correlated with reduced diastolic dysfunction. This variant has also been observed in patients with HCM outside of South Africa. Van Driest et al (2004) observed the variant in 2 of 389 patients with HCM, ancestry not reported. The variant was reported in a paper from Carolyn Ho's group on echo and MRI phenotyping in sarcomere variant carriers who do not yet have a diagnosis of HCM (Valente et al 2013). Presumably the variant was first identified in a patient with HCM, though that is not explicitly stated in the paper. Kassen et al (2013) observed the variant in 1 of 192 HCM patients in their Egyptian cohort. Nunez et al (2013) observed the variant in 2 of 104 HCM patients in their Spanish cohort. One of the patients also carried p.Arg1022Pro in MYBPC3. Multiple disease associated variants have been reported at either the same or nearby codons (p.Ala797Pro and p. Lue796Phe) (CardioGenomics Conservation analysis indicates that Alanine is partially conserved at this position across species. In silico analysis predicts the variant to be tolerated (SIFT) or benign (polyphen). In total the variant has been seen in ~5/7402 published controls and individuals from publicly available population datasets. The variant was recently reported online in 1 of 2206 African-American individuals and 0 of 4300 Caucasian individuals in the NHLBI Exome Sequencing Project dataset (as of December 19th, 2013). The phenotype of that individual is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). It is also listed in dbSNP (rs3218716) with the following frequencies in the relevant HapMap samples: 0/60 Caucasians, 1/43 Chinese individuals, 1/86 Japanese individuals, 0/60 African individuals, 1/46 Mexican individuals, 1/88 Italian individuals. The inconsistency between the ESP Caucasian data and the HapMap Caucasian data is curious. We would most likely put more weight on the ESP data. The variant was not observed in the following published control samples: Moolman et al (1995) did not identify the variant in 56 Caucasian and 54 mixed ancestry controls. Van Driest et al (2004) did not observe the variant in 100 African American and 100 Caucasian control samples from Coriell. Nunez et al (2013) did not observe the variant in 200 control individuals. GeneDx input 2011/12?: No, you’re not “that counselor” ? I think it’s good that we can share this info – it’s not getting any easier, that’s for sure. We literally just discussed this one last week. We had discussed changing our interpretation to a VUS, but again, the reported literature won out over the low frequency in dbSNP/1000 Genomes (I think some of that is the same HapMap data, if I’m remembering right). After a review of everyone we’ve seen it in, A797T was present in two sets of affected (HCM) relatives in two families as an isolated mutation (ages of dx ranging from teens to 60s). A third family also had two affected relatives with A797T, but they also had an MYBPC3 nonsense mutation and we can’t make much of that. The remaining cases provided no clinical info on family members, so we don’t have any other segregation/non-segregation data. This one could end up following 998, but Sherri felt strongly that we cannot over-rule the literature with the low frequency population data. That said, we’re keeping an eye on this one. I just came across a similar situation for a LQTS mutation that had reported just once, but with such extensive functional studies and co-segregation with a specific phenotype in a 3 generation pedigree – and then I saw it was reported in 2/180 alleles from indiv. of Hispanic ancestry in 1000 Genomes. Seems too high to be a real mutation, but I contacted the researcher who first reported it and he only had more conclusive information to share (as I probably should have guessed). So we’re continuing to work on how to interpret these accurately, and with the acknowledgement we don’t know the whole story… I wish I had something more helpful to add, but I’ll have to wait and see if we end up getting more conclusive evidence that would affect how we’re reporting A797T. ~Amy
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000656214 SCV000678408 likely pathogenic Wolff-Parkinson-White pattern 2017-07-14 no assertion criteria provided research This variant was identified in an individual with Wolff-Parkinson-White syndrome
Gharavi Laboratory,Columbia University RCV000158532 SCV000809472 pathogenic not provided 2018-09-16 no assertion criteria provided research

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