Submissions for variant NM_001267550.2(TTN):c.66491A>T (p.Lys22164Ile)

gnomAD frequency: 0.00016  dbSNP: rs371081043

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152250	SCV000201064	uncertain significance	not specified	2013-10-31	criteria provided, single submitter	clinical testing	The Lys19596Ile variant in TTN has not been reported in individuals with cardiom yopathy. It has been identified in 2/3696 African American chromosomes by the NH LBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). 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 clinical significance of the Lys19596Ile variant.
Invitae	RCV000229659	SCV000286788	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000733490	SCV000619005	uncertain significance	not provided	2017-07-11	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TTN gene. The c.61568 A>T (K20523I) variant has not been published as pathogenic or been reported as benign to our knowledge. This variant was observed in 5/7,594 (0.07%) alleles from individuals of African ancestry in the Exome Aggregation Consortium (Lek et al., 2016).The c.61568 A>T (K20523I) substitution occurs at a nucleotide position that is conserved across species. In silico splicing algorithms predict this variant creates a cryptic splice acceptor site 30bp downstream of the natural splice acceptor site in exon 266 of the TTN gene; however, in the absence of functional mRNA studies, the physiological consequence of this variant on splicing cannot be precisely determined. At the protein level, the c.61568 A>T (K20523I) variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Moreover, this substitution occurs at an amino acid position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Eurofins Ntd Llc (ga)	RCV000733490	SCV000861566	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001132863	SCV001292542	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-28	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	RCV001132864	SCV001292543	uncertain significance	Dilated cardiomyopathy 1G	2017-04-28	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	RCV001132865	SCV001292544	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2017-04-28	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	RCV001132866	SCV001292545	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2017-05-15	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	RCV001136277	SCV001296106	benign	Tibial muscular dystrophy	2017-05-15	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.
Ambry Genetics	RCV002372001	SCV002623755	uncertain significance	Cardiovascular phenotype	2019-03-04	criteria provided, single submitter	clinical testing	The p.K13099I variant (also known as c.39296A>T), located in coding exon 143 of the TTN gene, results from an A to T substitution at nucleotide position 39296. The lysine at codon 13099 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000733490	SCV003821739	uncertain significance	not provided	2021-05-24	criteria provided, single submitter	clinical testing