rs371069660
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The NM_017617.5(NOTCH1):c.6938G>A(p.Arg2313Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000676 in 1,612,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R2313W) has been classified as Likely benign.
Frequency
Consequence
NM_017617.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NOTCH1 | NM_017617.5 | c.6938G>A | p.Arg2313Gln | missense_variant | 34/34 | ENST00000651671.1 | |
NOTCH1 | XM_011518717.3 | c.6215G>A | p.Arg2072Gln | missense_variant | 31/31 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NOTCH1 | ENST00000651671.1 | c.6938G>A | p.Arg2313Gln | missense_variant | 34/34 | NM_017617.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000890 AC: 22AN: 247306Hom.: 0 AF XY: 0.0000889 AC XY: 12AN XY: 134966
GnomAD4 exome AF: 0.0000637 AC: 93AN: 1460570Hom.: 0 Cov.: 31 AF XY: 0.0000661 AC XY: 48AN XY: 726596
GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74362
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 03, 2023 | The p.R2313Q variant (also known as c.6938G>A), located in coding exon 34 of the NOTCH1 gene, results from a G to A substitution at nucleotide position 6938. The arginine at codon 2313 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in an individual with hypoplastic left heart syndrome and classified as variant of unknown significance (Kerstjens-Frederikse WS et al. Genet. Med., 2016 Sep;18:914-23). This amino acid position is well conserved in available vertebrate species; however, glutamine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2023 | Identified in a patient with hypoplastic left heart syndrome in published literature (Kerstjens-Frederikse et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26820064) - |
Aortic valve disease 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Sep 04, 2023 | - - |
Adams-Oliver syndrome 5 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Nov 12, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at