Submissions for variant NM_001267550.2(TTN):c.9512A>G (p.Asn3171Ser)

gnomAD frequency: 0.00006  dbSNP: rs139992576

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000251789	SCV000319011	uncertain significance	Cardiovascular phenotype	2013-11-25	criteria provided, single submitter	clinical testing	The p.N3171S variant (also known as c.9512A>G) is located in coding exon 40 of the TTNgene. This alteration results from an A to G substitution at nucleotide position 9512. The asparagine at codon 3171 is replaced by serine, an amino acid with highly similar properties. This variant was previously reported in dbSNP asrs139992576. Based on data from the NHLBI Exome Sequencing Project (ESP), the G-allele has an overall frequency of approximately0.01% (1/13006), having been observed in0.01% (1/8600)of European American alleles, and not observed in 4406 African American alleles studied. Based on data from the 1000 Genomes Project, the G-allele has an overall frequency of approximately0.05% (1/2184), having been observed in0.56% (1/178) of Japanesechromosomes studied. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging by PolyPhen in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae	RCV000541705	SCV000643933	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with serine at codon 3171 of the TTN protein (p.Asn3171Ser). There is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs139992576, ExAC 0.02%) but has not been reported in the literature in individuals with a TTN-related disease. ClinVar contains an entry for this variant (Variation ID: 263726). This variant identified in the TTN gene is located in the I band of the resulting protein (PMID: 25589632). It is unclear how this variant impacts the function of this protein. Algorithms developed to predict the effect of missense changes on protein structure and function are unavailable for the TTN gene. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on splicing. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Eurofins Ntd Llc (ga)	RCV000727950	SCV000855464	uncertain significance	not provided	2017-07-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001133396	SCV001293092	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	RCV001133397	SCV001293093	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	RCV001133398	SCV001293094	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	RCV001133399	SCV001293095	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	RCV001133400	SCV001293096	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.
GeneDx	RCV000727950	SCV001792621	uncertain significance	not provided	2019-05-20	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, predicts the creation of a cryptic splice donor site upstream of the natural splice donor site for intron 41; however, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown
Mayo Clinic Laboratories, Mayo Clinic	RCV000727950	SCV002541985	uncertain significance	not provided	2021-11-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417863	SCV004115175	uncertain significance	TTN-related condition	2022-12-10	criteria provided, single submitter	clinical testing	The TTN c.9512A>G variant is predicted to result in the amino acid substitution p.Asn3171Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179631299-T-C). 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	RCV003479083	SCV004223400	uncertain significance	not specified	2023-11-06	criteria provided, single submitter	clinical testing	Variant summary: TTN c.9512A>G (p.Asn3171Ser) results in a conservative amino acid change located in the I-band domain 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 6.8e-05 in 250758 control chromosomes (gnomAD). c.9512A>G has been reported in the literature in one individual affected with Brugada Syndrome (Scumaci_2018). The report does not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Type 2J. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29956481). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as benign (n=1) and uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000727950	SCV001552177	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TTN p.Asn3171Ser variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs139992576) and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and EGL Genetic Diagnostics). The variant was identified in control databases in 17 of 250758 chromosomes at a frequency of 0.00006779 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 15 of 113178 chromosomes (freq: 0.000133), African in 1 of 16256 chromosomes (freq: 0.000062) and South Asian in 1 of 30614 chromosomes (freq: 0.000033), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The p.Asn3171 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.