rs369167555
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_017617.5(NOTCH1):c.7397C>T(p.Thr2466Met) variant causes a missense change. The variant allele was found at a frequency of 0.000138 in 1,593,292 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152234Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000416 AC: 9AN: 216528Hom.: 0 AF XY: 0.0000423 AC XY: 5AN XY: 118182
GnomAD4 exome AF: 0.000145 AC: 209AN: 1440940Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 106AN XY: 714784
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152352Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74504
ClinVar
Submissions by phenotype
not provided Uncertain:4
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The NOTCH1 p.Thr2466Met variant was identified in the literature in a patient with hypoplastic left heart syndrome (Kerstjens-Frederikse_2016_PMID:26820064). The variant was identified in dbSNP (ID: rs369167555) and ClinVar (classified as uncertain significance by Invitae and GeneDx). The variant was identified in control databases in 9 of 216528 chromosomes at a frequency of 0.00004157 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 8 of 98176 chromosomes (freq: 0.000081) and Latino in 1 of 30988 chromosomes (freq: 0.000032), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Thr2466 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -
Reported in a Dutch individual with hypoplastic left heart syndrome, however, it was also found in this individual's father who had a normal echocardiogram (PMID: 26820064); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26096009, 26820064, 34387215) -
Adams-Oliver syndrome 5 Uncertain:1Benign:1
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NOTCH1-related disorder Uncertain:1
The NOTCH1 c.7397C>T variant is predicted to result in the amino acid substitution p.Thr2466Met. This variant, interpreted as likely benign, has been reported in patient with hypoplastic left heart syndrome and was found to be inherited from a father with a normal echocardiogram (Table S1 in Kerstjens-Frederikse et al. 2016. PubMed ID: 26820064). This variant is reported in 0.0081% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-139390794-G-A). This variant has been interpreted as uncertain by multiple submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/241169/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
The p.T2466M variant (also known as c.7397C>T), located in coding exon 34 of the NOTCH1 gene, results from a C to T substitution at nucleotide position 7397. The threonine at codon 2466 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in an individual with hypoplastic left heart syndrome (Kerstjens-Frederikse WS et al. Genet. Med., 2016 09;18:914-23). This amino acid position is 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. -
Aortic valve disease 1 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at