Submissions for variant NM_145690.3(YWHAZ):c.689C>G (p.Ser230Trp)

dbSNP: rs1554612377

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000517158	SCV000616330	uncertain significance	not specified	2017-09-26	criteria provided, single submitter	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197430	SCV001368164	pathogenic	See cases	2019-07-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS2,PS3,PM2,PP3.
Illumina Laboratory Services, Illumina	RCV003314604	SCV004014665	likely pathogenic	YWHAZ-related neurodevelopmental syndrome	2023-02-20	criteria provided, single submitter	clinical testing	The YWHAZ c.689C>G (p.Ser230Trp) missense variant results in the substitution of serine at amino acid position 230 with tryptophan. This variant has been reported in a heterozygous state in a nine year old male with a clinical diagnosis of cardiofaciocutaneous syndrome. The variant occurred de novo. The individual's phenotype included short stature, global developmental delay, dysmorphic facial features, coarse, curly hair, sparse eyebrows, pulmonic stenosis, hyperkeratosis, seizures and autistic-like and self-injurious behavior (PMID: 31024343). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Ectopic expression of c.689C>G RNA in Xenopus embryos resulted in severe head and body axis malformations compared to wild type. Co-overexpression of the c.689C>G variant RNA with c-raf RNA in the same model induced elevated Erk phosphorylation compared to wild type (PMID: 31024343). This variant was identified in a de novo state. Based on the available evidence, the c.689C>G (p.Ser230Trp) variant is classified as likely pathogenic for YWHAZ-related neurodevelopmental syndrome.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV003987577	SCV004804812	likely pathogenic	Noonan-like disorder	2023-09-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001089758	SCV005819411	pathogenic	not provided	2024-03-28	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 230 of the YWHAZ protein (p.Ser230Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cardio-facio-cutaneous syndrome (PMID: 31024343). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 448894). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt YWHAZ protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects YWHAZ function (PMID: 31024343). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000778073	SCV000914211	uncertain significance	Reclassified - variant of unknown significance	2021-12-23	no assertion criteria provided	literature only
GenomeConnect - CFC International	RCV001089758	SCV001245251	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 10-27-2017 by Lab or GTR ID 167595. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.
GenomeConnect, ClinGen	RCV001089758	SCV002029124	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 10-27-2017 by Lab or GTR ID 167595. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.