Submissions for variant NM_001267550.2(TTN):c.31735A>C (p.Lys10579Gln)

gnomAD frequency: 0.00003  dbSNP: rs376287951

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172366	SCV000055035	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000222100	SCV000272622	uncertain significance	not specified	2015-06-25	criteria provided, single submitter	clinical testing	The p.Lys9335Gln variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 7/8600 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s376287951). Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, the cli nical significance of the p.Lys9335Gln variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548036	SCV000642972	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-04-20	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000172366	SCV000705228	uncertain significance	not provided	2017-01-11	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001132692	SCV001292360	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	RCV001132693	SCV001292361	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	RCV001132694	SCV001292362	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	RCV001132695	SCV001292363	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.
Illumina Laboratory Services, Illumina	RCV001132696	SCV001292364	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.
PreventionGenetics, part of Exact Sciences	RCV004535175	SCV004120733	uncertain significance	TTN-related disorder	2022-09-28	criteria provided, single submitter	clinical testing	The TTN c.31735A>C variant is predicted to result in the amino acid substitution p.Lys10579Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.087% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179556770-T-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000222100	SCV004223688	uncertain significance	not specified	2023-11-10	criteria provided, single submitter	clinical testing	Variant summary: TTN c.28003A>C (p.Lys9335Gln) results in a conservative amino acid change located in the I-band region of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 248950 control chromosomes. To our knowledge, no occurrence of c.28003A>C in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J, or other TTN-related diseases and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=4; Benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000172366	SCV004237394	uncertain significance	not provided	2023-05-19	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001132692	SCV005398448	uncertain significance	Dilated cardiomyopathy 1G	2019-08-28	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_001267550.1(TTN):c.31735A>C in exon 121 of 363 of the TTN gene. (NB: This variant is non-coding in NM_003319.4.) This substitution is predicted to create a minor amino acid change from lysine to glutamine at position 10579 of the protein, NP_001254479.1(TTN):p.(Lys10579Gln). The lysine at this position has moderate conservation (100 vertebrates, UCSC), and is located within the PEVK 2 repeat region. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, CADD, Mutation Taster). The variant is present in the gnomAD population database at frequencies of 0.09% (17 heterozygotes, 0 homozygotes) and 0.008% (23 heterozygotes, 0 homozygotes) in the East Asian subpopulation and the global population, respectively. It has been previously reported as a VUS in clinical cases (ClinVar, LOVD). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).
Clinical Genetics, Academic Medical Center	RCV000172366	SCV001919165	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000172366	SCV001973677	uncertain significance	not provided		no assertion criteria provided	clinical testing