ClinVar Miner

Submissions for variant NM_001103.3(ACTN2):c.2147C>T (p.Thr716Met) (rs193922635)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000172894 SCV000223885 uncertain significance Familial hypertrophic cardiomyopathy 1 2015-03-20 criteria provided, single submitter research The ACTN2 Thr716Met variant has been previously reported to occur in the Exome Aggregation Consortium dataset ( at a frequency of 0.0003, and sub-population frequency of European (non-Finnish) individuals at 0.00059 (39/66254 alleles). The variant is absent in the 1000 genomes project ( Threonine (Thr) at position 716 is relatively conserved across distantly related species, and in silico tools are supportive of a damaging effect (SIFT "deleterious"; PolyPhen2 "probably damaging"; MutationTaster "disease-causing"; CADD score = 19), however this alone cannot be considered as strong evidence for pathogenicity. We have identified the ACTN2 Thr716Met variant in a single HCM proband of European descent. The patient was diagnosed aged 50 years, with asymmetric septal hypertophy of 20mm, and no established family history of disease. Based on the limited evidence, we call this variant one of "uncertain significance".
Ambry Genetics RCV000251944 SCV000320657 uncertain significance Cardiovascular phenotype 2017-07-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000029298 SCV000901191 uncertain significance Cardiomyopathy 2017-09-22 criteria provided, single submitter clinical testing
GeneDx RCV000766343 SCV000235697 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing The T716M variant of uncertain significance in the ACTN2 gene has not been published in association with cardiomyopathy to our knowledge. However, the T716M variant has been identified independently and in conjunction with additional cardiogenetic variants in multiple individuals referred for cardiomyopathy genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. Moreover, the T716M variant is observed in 39/125,816 (0.03%) European (non-Finnish) alleles, and in 56/10,120 (0.5%) Ashkenazi Jewish alleles in large population cohorts (Lek et al., 2016). Nevertheless, the T716M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Integrated Genetics/Laboratory Corporation of America RCV000029298 SCV000051944 uncertain significance Cardiomyopathy 2015-10-02 no assertion criteria provided clinical testing
Invitae RCV000228927 SCV000285866 benign Dilated cardiomyopathy 1AA; Primary familial hypertrophic cardiomyopathy 2017-11-09 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036896 SCV000060551 uncertain significance not specified 2015-02-25 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Thr716Met var iant in ACTN2 has been previously identified by our laboratory in 4 individuals with a range of cardiac features (1 adult with HCM, 1 adult with ARVC, 1 adolesc ent with mitral valve prolapse, and 1 adult with LVH and a mildly dilated LA). I t has also been identified in 0.1% (39/66254) of European chromosomes by the Exo me Aggregation Consortium (ExAC,; dbSNP rs1939226 35). Computational prediction tools and conservation analysis do not provide str ong support for or against an impact to the protein. In summary, while the clini cal significance of the p.Thr716Met variant is uncertain, these data suggest tha t it is more likely to be benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000624427 SCV000740540 uncertain significance Primary familial hypertrophic cardiomyopathy 2017-04-06 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000766343 SCV000925028 uncertain significance not provided 2016-01-28 no assertion criteria provided provider interpretation

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