Submissions for variant NM_017617.5(NOTCH1):c.6685G>A (p.Val2229Met)

gnomAD frequency: 0.00021  dbSNP: rs202096917

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001798762	SCV000320621	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2020-10-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467175	SCV000548950	likely benign	Adams-Oliver syndrome 5	2024-01-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001311043	SCV001501068	likely benign	not provided	2020-08-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001311043	SCV001817696	likely benign	not provided	2021-01-14	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25931334, 24113472)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798762	SCV002043541	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2019-10-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000467175	SCV002553835	likely benign	Adams-Oliver syndrome 5	2022-03-15	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002270195	SCV002553837	likely benign	Aortic valve disease 1	2022-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001701928	SCV005394352	likely benign	not specified	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: NOTCH1 c.6685G>A (p.Val2229Met) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 245566 control chromosomes. The observed variant frequency is approximately 287 fold of the estimated maximal expected allele frequency for a pathogenic variant in NOTCH1 causing Adams-Oliver Syndrome 5 phenotype (6.3e-07). ClinVar contains an entry for this variant (Variation ID: 264594). Based on the evidence outlined above, the variant was classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001311043	SCV001741248	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001311043	SCV001807744	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001701928	SCV001932886	benign	not specified		no assertion criteria provided	clinical testing