Submissions for variant NM_004387.4(NKX2-5):c.355G>T (p.Ala119Ser)

gnomAD frequency: 0.00090  dbSNP: rs137852684

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001529235	SCV000223570	likely benign	not provided	2020-09-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23285148, 24376681, 23661673, 27207958, 16418214, 28387797, 28798025, 31147515)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230156	SCV000288517	benign	Atrial septal defect 7	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000620259	SCV000735072	likely benign	Cardiovascular phenotype	2022-01-19	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000171007	SCV000917901	benign	not specified	2018-04-02	criteria provided, single submitter	clinical testing	Variant summary: NKX2-5 c.355G>T (p.Ala119Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 259522 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 194.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NKX2-5 causing Congenital Heart Disease phenotype (5e-06), strongly suggesting that the variant is benign. The variant, c.355G>T has been reported in the literature in individuals affected with Congenital Heart Disease, and the same publication reports experimental evidence evaluating an impact on protein function that showed variant behaves equal to wildtype NKX2-5 (vanEngelen_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV001529235	SCV002545376	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	NKX2-5: PM5, BS1
OMIM	RCV000009584	SCV000029802	pathogenic	Hypothyroidism, congenital, nongoitrous, 5	2006-04-01	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529235	SCV001742342	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001529235	SCV001917127	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529235	SCV001970120	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003904824	SCV004720721	likely benign	NKX2-5-related disorder	2021-03-05	no assertion criteria provided	clinical testing	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).