VCV000448894.15 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 448894 Accession: VCV000448894.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q22.3 8: 100920742 (GRCh38) [ NCBI UCSC ] 8: 101932970 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 19, 2017	Mar 30, 2024	Sep 29, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_145690.3:c.689C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_663723.1:p.Ser230Trp	missense
NM_001135699.2:c.689C>G	NP_001129171.1:p.Ser230Trp	missense
NM_001135700.2:c.689C>G	NP_001129172.1:p.Ser230Trp	missense
NM_001135701.2:c.689C>G	NP_001129173.1:p.Ser230Trp	missense
NM_001135702.2:c.689C>G	NP_001129174.1:p.Ser230Trp	missense
NM_003406.4:c.689C>G	NP_003397.1:p.Ser230Trp	missense
NC_000008.11:g.100920742G>C
NC_000008.10:g.101932970G>C

... more HGVS ... less HGVS

Protein change

S230W

Other names

Canonical SPDI

NC_000008.11:100920741:G:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

OMIM: 601288.0001 dbSNP: rs1554612377 ClinGen: CA371640357 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
YWHAZ		-	-	GRCh38 GRCh37	32	74

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Uncertain significance (1)	criteria provided, single submitter	Sep 26, 2017	RCV000517158.2
not provided	Uncertain significance (1)	no assertion criteria provided	Dec 23, 2021	RCV000778073.6
not provided	not provided (2)	no classification provided	-	RCV001089758.2
See cases	Pathogenic (1)	criteria provided, single submitter	Jul 1, 2019	RCV001197430.2
YWHAZ-related neurodevelopmental syndrome	Likely pathogenic (1)	criteria provided, single submitter	Feb 20, 2023	RCV003314604.1
Noonan-like disorder	Likely pathogenic (1)	criteria provided, single submitter	Sep 29, 2023	RCV003987577.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	see cases Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001368164.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS2,PS3,PM2,PP3. Clinical Features: Cryptorchidism (present) , Scrotal hypoplasia (present) , Hydronephrosis (present) , Pectus carinatum (present) , Global developmental delay (present) , Generalized hypotonia (present) , Pulmonary artery … (more) Cryptorchidism (present) , Scrotal hypoplasia (present) , Hydronephrosis (present) , Pectus carinatum (present) , Global developmental delay (present) , Generalized hypotonia (present) , Pulmonary artery stenosis (present) , Unusual dermatoglyphics (present) (less)
Uncertain significance (Sep 26, 2017)	criteria provided, single submitter (HA_AGHI_assertions_20171208) Method: research	not specified Affected status: yes Allele origin: de novo	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: AGHI-WGS-HudsonAlpha Accession: SCV000616330.2 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022	Number of individuals with the variant: 1 Clinical Features: Pulmonic stenosis (present) , Hydrocephalus (present) , Feeding difficulties (present) , Gastroesophageal reflux (present) , Otitis media (present) , Hyperkeratosis (present) , Dry skin (present) … (more) Pulmonic stenosis (present) , Hydrocephalus (present) , Feeding difficulties (present) , Gastroesophageal reflux (present) , Otitis media (present) , Hyperkeratosis (present) , Dry skin (present) , Scoliosis (present) , Decreased antibody level in blood (present) , Lymphopenia (present) , Ptosis (present) , Proptosis (present) , Thick vermilion border (present) , High forehead (present) , Triangular face (present) , Coarse hair (present) , Curly hair (present) , Abnormal facial shape (present) , Abnormal heart morphology (present) , Short stature (present) , Failure to thrive (present) (less)
Likely pathogenic (Feb 20, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	YWHAZ-related neurodevelopmental syndrome Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV004014665.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (1) PubMed: 31024343 Comment: 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 … (more) 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. (less)
Likely pathogenic (Sep 29, 2023)	criteria provided, single submitter (ACGS Guidelines, 2020) Method: clinical testing	Noonan-like disorder Affected status: yes Allele origin: de novo	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues Accession: SCV004804812.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024
Uncertain significance (Dec 23, 2021)	no assertion criteria provided Method: literature only	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000914211.3 First in ClinVar: May 27, 2019 Last updated: Dec 25, 2021	Publications: PubMed (1) PubMed: 31024343 Hiatt, S. Personal Communication. (more...) Hiatt, S. Personal Communication. 2019. Huntsville, Ala. Comment on evidence: This variant, previously designated POPOV-CHANG SYNDROME based on the report by Popov et al. (2019), has been reclassified at the request of the authors (Hiatt, … (more) This variant, previously designated POPOV-CHANG SYNDROME based on the report by Popov et al. (2019), has been reclassified at the request of the authors (Hiatt, 2019). In a 9-year-old boy (patient 1) with a neurodevelopmental disorder, Popov et al. (2019) identified a de novo heterozygous c.689C-G transversion (c.689C-G, NM_145690.2) in the YWHAZ gene, resulting in a ser230-to-trp (S230W) substitution in helix 6. The mutation, which was found by trio-based whole-genome sequencing, was not present in the gnomAD database. Detailed functional expression studies in Xenopus indicated that the S230W mutation resulted in a gain-of-function effect with increased activity of the Ras-Erk signaling pathway compared to wildtype. Studies of patient cells were not performed. The patient also carried a heterozygous frameshift variant (c.4022_4023insGA) in the SCN8A gene (600702). (less)
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect - CFC International Accession: SCV001245251.1 First in ClinVar: May 04, 2020 Last updated: May 04, 2020	Comment: 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 … (more) 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. (less) Clinical Features: Aplasia/Hypoplasia of the ear (present) , Oral cleft (present) , Abnormal facial shape (present) , Abnormality of the nose (present) , Abnormality of cardiovascular system … (more) Aplasia/Hypoplasia of the ear (present) , Oral cleft (present) , Abnormal facial shape (present) , Abnormality of the nose (present) , Abnormality of cardiovascular system morphology (present) , Feeding difficulties (present) , Abnormality of muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the pelvis (present) , Hyperpigmentation of the skin (present) , Epidermal thickening (present) , Morphological abnormality of the central nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Seizures (present) , Immunodeficiency (present) , Recurrent infections (present) , Abnormal delivery (present) , Premature birth (present) , Autistic behavior (present) , Stereotypy (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: male Testing laboratory: PerkinElmer Genetics, Inc. Date variant was reported to submitter: 2017-10-27 Testing laboratory interpretation: Uncertain significance
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002029124.1 First in ClinVar: Dec 04, 2021 Last updated: Dec 04, 2021	Comment: 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 … (more) 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. (less) Clinical Features: Abnormal delivery (present) , Premature birth (present) , Failure to thrive (present) , Decreased response to growth hormone stimulation test (present) , Orofacial cleft (present) … (more) Abnormal delivery (present) , Premature birth (present) , Failure to thrive (present) , Decreased response to growth hormone stimulation test (present) , Orofacial cleft (present) , Abnormal facial shape (present) , Abnormal hair morphology (present) , Abnormality of the nose (present) , Abnormal skull morphology (present) , Abnormality of eye movement (present) , Abnormality of vision (present) , Abnormal optic nerve morphology (present) , Ptosis (present) , Ear malformation (present) , Hyperacusis (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , EEG abnormality (present) , Generalized hypotonia (present) , Seizure (present) , Autistic behavior (present) , Motor stereotypies (present) , Anxiety (present) , Atrophic scars (present) , Cafe au lait spots, multiple (present) , Hyperpigmentation of the skin (present) , Thickened skin (present) , Abnormal curvature of the vertebral column (present) , Pectus excavatum (present) , Abnormal muscle physiology (present) , Abnormal cardiovascular system morphology (present) , Hypertensive disorder (present) , Feeding difficulties (present) , Abnormal esophagus morphology (present) , Gastrointestinal dysmotility (present) , Abnormality of the male genitalia (present) , Immunodeficiency (present) , Recurrent infections (present) , Bruising susceptibility (present) , Abnormal leukocyte morphology (present) (less) Age: 0-9 years Sex: male Testing laboratory: PerkinElmer Genomics Date variant was reported to submitter: 2017-10-27 Testing laboratory interpretation: Uncertain significance

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A YWHAZ Variant Associated With Cardiofaciocutaneous Syndrome Activates the RAF-ERK Pathway.	Popov IK	Frontiers in physiology	2019	PMID: 31024343
Hiatt, S. Personal Communication. 2019. Huntsville, Ala.	-	-	-	-

Text-mined citations for rs1554612377 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1554612377 ...