Submissions for variant NM_001267550.2(TTN):c.82402A>C (p.Lys27468Gln)

gnomAD frequency: 0.00027  dbSNP: rs201958805

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040681	SCV000064372	uncertain significance	not specified	2013-01-28	criteria provided, single submitter	clinical testing	The Lys24900Gln variant in TTN has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 4/8240 E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/, dbSNP rs201958805). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, and PolyP hen2) suggest that this variant may not impact the protein, though this informat ion is not predictive enough to rule out pathogenicity. Additional information i s needed to fully assess the clinical significance of this variant.
GeneDx	RCV000997376	SCV000236792	likely benign	not provided	2021-05-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000353764	SCV000421393	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2018-01-12	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	RCV000300172	SCV000421395	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2018-01-12	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	RCV000357436	SCV000421396	uncertain significance	Dilated cardiomyopathy 1G	2018-01-12	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	RCV000787943	SCV000421397	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-01-12	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	RCV000322064	SCV000421398	benign	Tibial muscular dystrophy	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456607	SCV000542840	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-29	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768905	SCV000900278	likely benign	Cardiomyopathy	2020-09-18	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000787943	SCV000926964	likely benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-12-05	criteria provided, single submitter	clinical testing	A heterozygous c.55018C>T (p.R18340X) pathogenic variant in the TTN gene was detected in this individual. A heterozygous c.95252_95254delCAA (p.T31751del) likely pathogenic variant in the TTN gene was also detected. A heterozygous c.74698A>C (p.K24900Q) variant was also detected and found to be likely benign. The c.55018C>T (p.R18340X) variant is in trans configuration with the c.95252_95254delCAA (p.T31751del) and c.74698A>C (p.K24900Q) variants.
CeGaT Center for Human Genetics Tuebingen	RCV000997376	SCV001152715	likely benign	not provided	2022-08-01	criteria provided, single submitter	clinical testing	TTN: BP4, BS2
Ambry Genetics	RCV002345318	SCV002648701	uncertain significance	Cardiovascular phenotype	2018-12-21	criteria provided, single submitter	clinical testing	The p.K18403Q variant (also known as c.55207A>C), located in coding exon 153 of the TTN gene, results from an A to C substitution at nucleotide position 55207. The lysine at codon 18403 is replaced by glutamine, an amino acid with similar properties. This amino acid position is not well 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	RCV000997376	SCV003827378	uncertain significance	not provided	2023-03-30	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000040681	SCV005622434	likely benign	not specified	2024-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040681	SCV005726818	likely benign	not specified	2024-11-11	criteria provided, single submitter	clinical testing	Variant summary: TTN c.74698A>C (p.Lys24900Gln), also reported as NM_001267550:c.82402A>C (p.Lys27468Gln), results in a conservative amino acid change located in the A-band 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 0.00027 in 248628 control chromosomes, predominantly at a frequency of 0.00055 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.41 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039). To our knowledge, no occurrence of c.74698A>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. In 1 individual affected with recessive TTN-related condition(s), this variant was in cis with a rare VUS (TTN c.95252_95254delCAA, p.T31751del) on 1 allele which was confirmed in trans with a pathogenic variant (TTN c.55018C>T, p.R18340X), suggesting a possibly benign role. ClinVar contains an entry for this variant (Variation ID: 47411). Based on the evidence outlined above, the variant was classified as likely benign.