NM_001267550.2:c.31757C>A
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_001267550.2(TTN):c.31757C>A(p.Pro10586Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,611,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P10586A) has been classified as Likely benign.
Frequency
Consequence
NM_001267550.2 missense
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | MANE Select | c.31757C>A | p.Pro10586Gln | missense | Exon 121 of 363 | NP_001254479.2 | ||
| TTN | NM_001256850.1 | c.30806C>A | p.Pro10269Gln | missense | Exon 119 of 313 | NP_001243779.1 | |||
| TTN | NM_133378.4 | c.28025C>A | p.Pro9342Gln | missense | Exon 118 of 312 | NP_596869.4 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | TSL:5 MANE Select | c.31757C>A | p.Pro10586Gln | missense | Exon 121 of 363 | ENSP00000467141.1 | ||
| TTN | ENST00000446966.2 | TSL:1 | c.31757C>A | p.Pro10586Gln | missense | Exon 121 of 361 | ENSP00000408004.2 | ||
| TTN | ENST00000436599.2 | TSL:1 | c.31481C>A | p.Pro10494Gln | missense | Exon 119 of 361 | ENSP00000405517.2 |
Frequencies
GnomAD3 genomes 0.000861 AC: 131AN: 152094Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000492 AC: 122AN: 247940 AF XY: 0.000401 show subpopulations
GnomAD4 exome AF: 0.000251 AC: 367AN: 1459366Hom.: 0 Cov.: 30 AF XY: 0.000230 AC XY: 167AN XY: 725894 show subpopulations
Age Distribution
GnomAD4 genome 0.000861 AC: 131AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.000820 AC XY: 61AN XY: 74410 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4
This variant is associated with the following publications: (PMID: 24503780, 27930701)
TTN: BP4
not specified Uncertain:1Benign:3
Variant summary: TTN c.28025C>A (p.Pro9342Gln) results in a non-conservative amino acid change located in the I band region (https://www.cardiodb.org/titin/) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00049 in 247940 control chromosomes, predominantly at a frequency of 0.0017 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.28025C>A has been reported in the literature in individuals affected with Sudden Infant Death Syndrome, Sudden Unexplained Death and Dilated Cardiomyopathy (Sanchez_2016, Pugh_2014, Campuzano_2015) without strong evidence of causality. These reports therefore, do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=4) or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as benign.
Variant classified as Uncertain Significance - Favor Benign. The p.Pro9342Gln in TTN has been previously identified by our laboratory in 1 Caucasian infant with DCM and 1 Black adult with HCM. This variant has also been identified in 0.16% (16/9754) of African chromosomes by the Exome Aggregation Consortium (ExAC, http ://exac.broadinstitute.org; dbSNP rs200459347). Computational prediction tools a nd conservation analysis suggest that this variant may not impact the protein, t hough this information is not predictive enough to rule out pathogenicity. In su mmary, while the clinical significance of the p.Pro9342Gln variant is uncertain, its frequency suggests that it is more likely to be benign.
Autosomal recessive limb-girdle muscular dystrophy type 2J Uncertain:1
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.
Dilated cardiomyopathy 1G Uncertain:1
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.
Early-onset myopathy with fatal cardiomyopathy Uncertain:1
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.
TTN-related disorder Benign:1
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).
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1
Cardiomyopathy Benign:1
Myopathy, myofibrillar, 9, with early respiratory failure Benign:1
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.
Tibial muscular dystrophy Benign:1
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.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at