ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.91621G>A (p.Gly30541Arg) (rs200854704)

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Total submissions: 10
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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 RCV000172620 SCV000051244 likely benign not provided 2013-06-24 criteria provided, single submitter research
Illumina Clinical Services Laboratory,Illumina RCV000374307 SCV000420901 uncertain significance Hypertrophic cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000282263 SCV000420902 uncertain significance Dilated Cardiomyopathy, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000316301 SCV000420903 uncertain significance Distal myopathy Markesbery-Griggs type 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000373589 SCV000420904 uncertain significance Hereditary myopathy with early respiratory failure 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000295443 SCV000420905 uncertain significance Limb-Girdle Muscular Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000352604 SCV000420906 uncertain significance Myopathy, early-onset, with fatal cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000457779 SCV000542803 uncertain significance Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J 2017-11-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000040782 SCV000064473 uncertain significance not specified 2017-07-20 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Gly27973Arg v ariant in TTN has been identified by our laboratory in 1 Caucasian adult with HC M and 1 Asian infant with DCM, both of whom carried an additional pathogenic var iant sufficient to cause their disease. It has also been identified in 23/276266 pan ethnic chromosomes by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org; dbSNP rs200854704). Computational prediction tools and con servation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Gly27973Arg varia nt is uncertain, these data suggest that it is more likely to be benign.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000172620 SCV000925004 uncertain significance not provided 2017-08-10 no assertion criteria provided provider interpretation p.Gly27973Arg) (c.83917G>A) in exon 286 of the TTN gene (NM_133378.4; Chr2:179414944C>T; GrCh37) Given that this variant has been seen in 2 individuals who both had other pathogenic variants identified on their tests at the testing lab, and its prevalence in the general population, we consider this variant a variant of uncertain significance, likely benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least 2 unrelated cases of cardiomyopathy (not including this patient's family). There is no case data in the literature available for review. This variant is reported in ClinVar. It is classified as a variant of uncertain significance by two other labs (Invitae and Illumina Clinical Services Laboratory), and likely benign by the NIH. LMM has seen this variant in 2 individuals: 1 Caucasian adult with HCM and 1 Asian infant with DCM, both of whom had an additional pathogenic variant sufficient to cause their disease. Per the test report, "computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein." This variant is almost conserved across more than 100 species, as are neighboring amino acids. The variant was reported online in 23 of 138,133 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 4 of 12,000 individuals of African descent (highest MAF=0.016%), 2 of 9,408 individuals of East Asian descent, 13 of 62,988 individuals of European descent, 2 of 15,387 individuals of South Asian descent, 1 of 17,202 individuals of Latino descent and 1 of 3,218 individuals of "other" descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Data suggests that a minor allele frequency below 0.004% is an appropriate threshold for considering a variant's pathogenicity in HCM given the rarity of the disease and its heterogeneity (Whiffen et al 2016).

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