Submissions for variant NM_001267550.2(TTN):c.54710T>C (p.Leu18237Pro)

gnomAD frequency: 0.00063  dbSNP: rs201412693

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172312	SCV000054986	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000172312	SCV000237304	likely benign	not provided	2021-02-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362, 32403337)
Ambry Genetics	RCV000242658	SCV000319109	uncertain significance	Cardiovascular phenotype	2013-10-07	criteria provided, single submitter	clinical testing	The p.L15669P variant (also known as c.47006T>C) is located in coding exon 230 of theTTNgene. This alteration results from a T to C substitution at nucleotide position 47006. The leucine at codon 15669 is replaced by proline, an amino acid with some similar properties. This variant was previously reported in dbSNP asrs201412693. Based on data from the NHLBI Exome Sequencing Project (ESP), the C-allele has an overall frequency of approximately 0.07% (8/12090), having been observed in0.08% (7/8262)of European American alleles, and in 00.03% (1/3828)of African American alleles studied. This variant was not reported in the 1000 Genomes Project. Based on protein sequence alignment, this amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Eurofins Ntd Llc (ga)	RCV000172312	SCV000332821	uncertain significance	not provided	2015-07-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000312071	SCV000422786	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000366773	SCV000422787	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000277068	SCV000422788	uncertain significance	Dilated cardiomyopathy 1G	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000313378	SCV000422789	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000354316	SCV000422790	benign	Tibial muscular dystrophy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV001082395	SCV000542513	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000259186	SCV000710954	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Leu15669Pro v ariant in TTN has not been previously reported in individuals with cardiomyopath y, but has been identified in 0.1% (141/126168) of European chromosomes by the g enome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs2 01412693). This variant has been reported in ClinVar (Variation ID: 191944) as o f uncertain significance or likely benign. Leucine (Leu) at position 15669 is no t conserved in mammals or evolutionarily distant species, supporting that a chan ge at this position may be tolerated. In summary, while the clinical significanc e of the p.Leu15669Pro variant is uncertain, these data suggest that it is more likely to be benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768993	SCV000900366	benign	Cardiomyopathy	2022-03-18	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000395819	SCV000995571	likely benign	Hypertrophic cardiomyopathy	2019-04-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000259186	SCV001879665	benign	not specified	2021-02-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000172312	SCV003823571	uncertain significance	not provided	2022-05-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000172312	SCV004011267	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TTN: BP4, BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000259186	SCV004100177	likely benign	not specified	2023-09-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535173	SCV004119938	uncertain significance	TTN-related disorder	2022-10-26	criteria provided, single submitter	clinical testing	The TTN c.54710T>C variant is predicted to result in the amino acid substitution p.Leu18237Pro. This variant was reported, along with a second TTN missense variant, in an individual with muscle weakness and asymmetric extensor finger (Patient #43 in Supplementary data, Gonzalez-Quereda et al. 2020. PubMed ID: 32403337). This variant was also reported, along with a de novo multi-exon TTN deletion, in an individual with skeletal myopathy, facial weakness, and dilated cardiomyopathy (Roggenbuck et al. 2019. PubMed ID: 31489791). This variant was also documented in an individual with cardiomyopathy; however, this individual also harbored compound heterozygous truncating variants in TTN (Patient #29 in Table S3, Rees et al. 2021. PubMed ID: 33449170). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179468704-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.