ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.5479G>T (p.Ala1827Ser)

gnomAD frequency: 0.00087  dbSNP: rs141213991
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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000172728 SCV000051506 likely benign not provided 2013-06-24 criteria provided, single submitter research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000040454 SCV000064145 benign not specified 2018-06-14 criteria provided, single submitter clinical testing The p.Ala1827Ser variant in TTN is classified as benign because it has been iden tified in 0.13% (165/126446) of European chromosomes by the Genome Aggregation D atabase (gnomAD, http://gnomad.broadinstitute.org/). ACMG/AMP Criteria applied: BA1.
Eurofins Ntd Llc (ga) RCV000172728 SCV000228655 uncertain significance not provided 2018-07-02 criteria provided, single submitter clinical testing
GeneDx RCV000172728 SCV000238006 likely benign not provided 2020-08-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26272908, 24033266, 23861362, 24503780)
Illumina Laboratory Services, Illumina RCV003329159 SCV000424979 uncertain significance TTN-Related Disorders 2023-05-02 criteria provided, single submitter clinical testing The TTN c.5479G>T (p.Ala1827Ser) variant is a missense variant located in exon 28 of the meta isoform NM_001267550 between the Z-disk and the I-band, and more specifically between the Ig-like-8 and Ig-like-9 domains. The p.Ala1827Ser variant is reported at a frequency of 0.00150 in the European (non-Finnish) population of the Genome Aggregation Database (gnomAD) v3.1.1 and is therefore considered a likely benign variant for all dominantly inherited TTN-related disorders. No homozygous control individuals have been reported for this variant in gnomAD v2.1.1 and 3.1.1. To our knowledge, this variant has not been reported in any TTN-related myopathies with extra-cardiac features, and thus the possibility that this variant contributes to recessive myopathy when found in homozygous or compound-heterozygous state with another variant cannot be excluded at this time. Based on the available evidence, the p.Ala1827Ser is classified as a variant of uncertain significance for recessively inherited TTN-related myopathy.
Invitae RCV001086722 SCV000555443 likely benign Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J 2024-01-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617741 SCV000735079 likely benign Cardiovascular phenotype 2019-11-21 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego RCV000852935 SCV000995680 likely benign Primary dilated cardiomyopathy; Heart failure 2018-07-03 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000172728 SCV001146435 likely benign not provided 2019-04-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000040454 SCV001748670 likely benign not specified 2021-06-21 criteria provided, single submitter clinical testing Variant summary: TTN c.5479G>T (p.Ala1827Ser) results in a conservative amino acid change located in the I-Band 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 0.00087 in 250448 control chromosomes, predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.58 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5479G>T has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Campuzano_2015, Mademont-Soler_2017, Pugh_2014). These reports do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen RCV000172728 SCV001962339 uncertain significance not provided 2021-12-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798169 SCV002042568 benign Cardiomyopathy 2020-06-08 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000329243 SCV000607069 not provided Tibial muscular dystrophy no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000172728 SCV001739818 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000040454 SCV001925160 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000172728 SCV001927595 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000172728 SCV001957409 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000172728 SCV001969775 likely benign not provided no assertion criteria provided clinical testing

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