Submissions for variant NM_001267550.2(TTN):c.45599C>G (p.Ala15200Gly)

gnomAD frequency: 0.00033  dbSNP: rs201057307

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000118756	SCV000051287	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000118756	SCV000063952	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	The p.Ala12632Gly variant in TTN has been reported in one heterozygous individual with hypertrophic cardiomyopathy and one compound heterozygous individual with myopathy (Lopes 2013 PMID: 23396983, Dabby 2015 PMID: 25772186). It has also been identified in 0.95% (33/3464) of Ashkenazi Jewish chromosomes and 0.016% (11/67906) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 46991). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS2_P, PP3.
Genetic Services Laboratory, University of Chicago	RCV000118756	SCV000153273	uncertain significance	not provided	2014-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000118756	SCV000237191	likely benign	not provided	2020-10-15	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27854229, 27854218, 25772186, 23861362, 23396983)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000040261	SCV000257866	uncertain significance	not specified	2015-07-10	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000040261	SCV000332760	benign	not specified	2017-07-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000767850	SCV000423229	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	RCV000385022	SCV000423231	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	RCV000282960	SCV000423232	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.
Illumina Laboratory Services, Illumina	RCV000986939	SCV000423233	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	RCV000378515	SCV000423234	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.
Invitae	RCV001085279	SCV000542858	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621910	SCV000736135	benign	Cardiovascular phenotype	2017-11-29	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Mendelics	RCV000986939	SCV001136098	benign	Dilated cardiomyopathy 1G	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000118756	SCV001152913	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	TTN: BP4, BS1, BS2
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149647	SCV003838618	benign	Cardiomyopathy	2021-06-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040261	SCV003934128	benign	not specified	2023-05-18	criteria provided, single submitter	clinical testing	Variant summary: TTN c.37895C>G (p.Ala12632Gly) results in a non-conservative amino acid change located in the I-band region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 247242 control chromosomes (gnomAD). The observed variant frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039) and within the Ashkenazi Jewish subpopulation it is seen at a frequency of 0.012, strongly suggesting that the variant is benign. c.37895C>G has been reported in the literature in settings of whole exome sequencing and multigene panel testing as a VUS in the heterozygous state in an individual affected with hypertrophic cardiomyopathy, and as a compound heterozygous genotype in two individuals with a myopathy phenotype without strong evidence for causality (e.g. Lopes_2013, Dabby_2015 Punetha_2016). Therefore, these reports do not provide unequivocal conclusions about association of the variant with disease. Additionally, a co-occurrence with a pathogenic variant has been observed (TTR c.148G>A, p.Val50Met; internal data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25772186, 23396983, 27854218). Eleven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either benign (n=7)/likely benign (1) or VUS (n=3). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004541155	SCV004788822	likely benign	TTN-related disorder	2022-08-26	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
OMIM	RCV000767850	SCV000898472	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2019-04-17	no assertion criteria provided	literature only