Submissions for variant NM_001267550.2(TTN):c.31837C>G (p.Pro10613Ala)

gnomAD frequency: 0.00033  dbSNP: rs200213832

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040128	SCV000063819	uncertain significance	not specified	2012-07-24	criteria provided, single submitter	clinical testing	The Pro9369Ala variant in TTN has not been reported in the literature nor previo usly identified by our laboratory. This variant has been identified in 1/8176 Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS/), though this could represent a pre symptomatic individual. Computational analyses (biochemical amino acid propertie s, conservation, AlignGVGD, PolyPhen2, and SIFT) do not argue for or against an impact to the protein. Additional information is needed to fully assess the clin ical significance of the Pro9369Ala variant.
Invitae	RCV000233950	SCV000286572	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-27	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000725168	SCV000334599	uncertain significance	not provided	2015-08-24	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000725168	SCV000616056	likely benign	not provided	2018-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000725168	SCV000730353	likely benign	not provided	2021-03-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24503780)
CeGaT Center for Human Genetics Tuebingen	RCV000725168	SCV001152989	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	TTN: BP4
Illumina Laboratory Services, Illumina	RCV001134533	SCV001294280	benign	Tibial muscular dystrophy	2017-04-27	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	RCV001134534	SCV001294281	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2017-04-27	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	RCV001134535	SCV001294282	uncertain significance	Dilated cardiomyopathy 1G	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001135959	SCV001295771	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-04-27	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	RCV001135960	SCV001295772	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-27	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.
Baylor Genetics	RCV001135960	SCV001525248	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2020-01-08	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040128	SCV002599001	likely benign	not specified	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: TTN c.28105C>G (p.Pro9369Ala) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 247188 control chromosomes, predominantly at a frequency of 0.00076 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2 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 Latino origin. c.28105C>G has been reported in the literature in an individual affected with Dilated Cardiomyopathy and an individual reported with Sudden Unexplained Death (Pugh_2014, Campuzano_2015). 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. The following publications have been ascertained in the context of this evaluation (PMID: 24503780, 26516846).Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=4) and VUS (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004528207	SCV004103586	uncertain significance	TTN-related disorder	2023-03-13	criteria provided, single submitter	clinical testing	The TTN c.28105C>G variant is predicted to result in the amino acid substitution p.Pro9369Ala. This variant has been reported in an individual with dilated cardiomyopathy and interpreted as uncertain significance (Table S3, referred to as g.179554549G>C/NM_133378.4:c.28105C>G, Pugh et al. 2014. PubMed ID: 24503780). This variant is reported in 0.077% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179554549-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.