Submissions for variant NM_001267550.2(TTN):c.54109C>T (p.Arg18037Trp)

gnomAD frequency: 0.00009  dbSNP: rs201623791

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000218519	SCV000272687	uncertain significance	not specified	2017-08-03	criteria provided, single submitter	clinical testing	The p.Arg15469Trp variant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 9/125506 European and 3/23972 A frican chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org, dbSNP rs201623791). Computational prediction tools and conserva tion analysis suggest that this variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, the cli nical significance of the p.Arg15469Trp variant is uncertain.
Invitae	RCV000473378	SCV000542516	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-05-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000834830	SCV000976601	likely benign	not provided	2020-09-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31983221)
Illumina Laboratory Services, Illumina	RCV001132764	SCV001292435	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001132765	SCV001292436	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	RCV001132766	SCV001292437	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001132767	SCV001292438	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	RCV001132768	SCV001292439	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000218519	SCV001442845	uncertain significance	not specified	2020-10-27	criteria provided, single submitter	clinical testing	Variant summary: TTN c.46405C>T (p.Arg15469Trp) results in a non-conservative amino acid change located in the A-band region of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 247652 control chromosomes, predominantly at a frequency of 8.9e-05 within the Non-Finnish European subpopulation in the gnomAD database. However, in certain European subpopulations the variant occurs with an even higher frequency, e.g. in North-western Europeans (allele frequency: 0.0002). This frequency somewhat lower than the maximum expected for a pathogenic variant in TTN causing Dilated Cardiomyopathy (0.00039), allowing no clear conclusions about variant significance. The variant, c.46405C>T, has been reported in the literature in individuals affected with Dilated Cardiomyopathy (Horvat_2018, Minoche_2018, Mazzarotto_2020). However, in a reported family, this variant didn't segregate with the disease, while a pathogenic variant (MYH7 c.1106G>A, p.Arg369Gln), which could explain the phenotype, segregated with the disease (Horvat_2018, Minoche_2018); these data provide supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (3x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV002450637	SCV002739782	likely benign	Cardiovascular phenotype	2022-10-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Revvity Omics, Revvity	RCV000834830	SCV003822845	uncertain significance	not provided	2019-07-10	criteria provided, single submitter	clinical testing