Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000155761 | SCV000205472 | uncertain significance | not specified | 2014-01-21 | criteria provided, single submitter | clinical testing | The Ser30419Leu variant in TTN has now been identified by our laboratory in 1 in fant with DCM and 1 adult with HCM. It was not identified in large population st udies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clin ical significance of the Ser30419Leu variant. |
Labcorp Genetics |
RCV000543884 | SCV000644002 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J | 2017-12-29 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000621722 | SCV000735614 | likely benign | Cardiovascular phenotype | 2023-02-01 | criteria provided, single submitter | clinical testing | 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. |
Fulgent Genetics, |
RCV000764302 | SCV000895321 | uncertain significance | Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Mayo Clinic Laboratories, |
RCV001508101 | SCV001714025 | uncertain significance | not provided | 2019-11-18 | criteria provided, single submitter | clinical testing | |
Gene |
RCV001508101 | SCV001825452 | likely benign | not provided | 2021-05-20 | criteria provided, single submitter | clinical testing | Observed in 21/125,412 (0.01%) alleles from individuals of European background (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25332820) |
Revvity Omics, |
RCV001508101 | SCV003824227 | uncertain significance | not provided | 2023-03-27 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000155761 | SCV003844826 | uncertain significance | not specified | 2023-02-15 | criteria provided, single submitter | clinical testing | Variant summary: TTN c.91255_91256delinsCT (p.Ser30419Leu) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9e-05 in 279158 control chromosomes. This frequency does not allow conclusions about variant significance. c.91255_91256delinsCT has been reported in the literature in individuals affected with dilated cardiomyopathy (Wasielewski_2014), hypertrophic cardiomyopathy (Burstein_2021), and pediatric-onset cardiomyopathy (Herkert_2020), however, co-segregation and co-occurrence data suggested the variant was not causative of disease in all cases. These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments; 4 submitters classified the variant as uncertain significance, and one submitter classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Prevention |
RCV004528891 | SCV004111701 | uncertain significance | TTN-related disorder | 2023-10-02 | criteria provided, single submitter | clinical testing | The TTN c.98959_98960delinsCT variant is predicted to result in an in-frame deletion and insertion. This variant has been reported in an individual with dilated cardiomyopathy (aka p.Ser31346Leu, Wasielewski et al. 2014. PubMed ID: 25332820) and an individual with hypertrophic cardiomyopathy (aka p.Ser30419Leu, Table S2, Burstein et al. 2021. PubMed ID: 32746448). This variant was also observed in an individual with severe cardiac defects; however, a sibling that was also affected did not carry the variant (aka p.Ser30419Leu, Family 7, Herkert et al. 2020. PubMed ID: 32480058). This variant is reported in 0.017% of alleles in individuals of European (non-Finnish) descent in gnomAD as a multi-nucleotide variant (https://gnomad.broadinstitute.org/variant/2-179403703-A-G; https://gnomad.broadinstitute.org/variant/2-179403702-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |