Submissions for variant NM_001267550.2(TTN):c.55374C>G (p.Ser18458Arg)

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Total submissions: 12

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000152301	SCV006066918	likely benign	not specified	2025-04-09	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000172660	SCV004225859	likely benign	not provided	2025-05-12	criteria provided, single submitter	clinical testing	BS1, BP4
Revvity Omics, Revvity	RCV000172660	SCV003821069	uncertain significance	not provided	2024-08-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002433662	SCV002747655	likely benign	Cardiovascular phenotype	2020-01-02	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798480	SCV002042543	likely benign	Cardiomyopathy	2020-03-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152301	SCV001821441	likely benign	not specified	2026-02-24	criteria provided, single submitter	clinical testing	Variant summary: TTN c.47670C>G (p.Ser15890Arg) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00064 in 1603408 control chromosomes, predominantly at a frequency of 0.00079 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for disease-causing variants in TTN. c.47670C>G has been observed in an individual affected with Dilated Cardiomyopathy (Roggenbuck_2019). However, this individual also had a co-occurring pathogenic variant (reported as NM_001267550.2 exons 346-362 deletion), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31489791). ClinVar contains an entry for this variant (Variation ID: 165969). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000172660	SCV001152871	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476468	SCV000542339	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-29	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000172660	SCV000333474	uncertain significance	not provided	2015-07-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000172660	SCV000237316	likely benign	not provided	2020-10-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152301	SCV000201168	uncertain significance	not specified	2014-08-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Ser15890Arg var iant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (10/8194) of European American chromosomes by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs20 0550947). Computational prediction tools and conservation analysis do not provid e strong support for or against an impact to the protein. In summary, while the clinical significance of the Ser15890Arg variant is uncertain, its frequency sug gests that it is more likely to be benign.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172660	SCV000054983	likely benign	not provided	2013-06-24	criteria provided, single submitter	research

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