Submissions for variant NM_001267550.2(TTN):c.9290T>C (p.Leu3097Pro)

dbSNP: rs373366126

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040899	SCV000064590	uncertain significance	not specified	2013-06-13	criteria provided, single submitter	clinical testing	The Leu3097Pro variant in TTN has been identified by our laboratory in 1 individ ual with palpitations and syncope and in 1 child with DCM (LMM unpublished data) . In addition, this variant has also been identified in 1/8600 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. Additional information is needed to fully assess the clinical significance of th is variant.
GeneDx	RCV001703915	SCV000238054	likely benign	not provided	2018-07-10	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26094658, 31983221)
Invitae	RCV000468674	SCV000542730	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2016-10-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001133509	SCV001293211	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-10-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001133510	SCV001293212	likely benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-10-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001133511	SCV001293213	uncertain significance	Dilated cardiomyopathy 1G	2017-10-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001133512	SCV001293214	benign	Tibial muscular dystrophy	2017-10-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001135007	SCV001294772	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2017-10-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001703915	SCV002541987	uncertain significance	not provided	2021-05-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040899	SCV002600420	uncertain significance	not specified	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: TTN c.9290T>C (p.Leu3097Pro) results in a non-conservative amino acid change located in the I-band of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251182 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9290T>C has been reported in the literature in individuals affected with Dilated Cardiomyopathy, without strong evidence for causality (Mazzarotto_2020). This report does 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three submitters classified the variant as likely benign/benign while three classified as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.