VCV000238218.23 - ClinVar

NM_001077415.3(CRELD1):c.575G>A (p.Cys192Tyr)

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.

(5)

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); Uncertain significance(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001077415.3(CRELD1):c.575G>A (p.Cys192Tyr)

Variation ID: 238218 Accession: VCV000238218.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.3 3: 9940964 (GRCh38) [ NCBI UCSC ] 3: 9982648 (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	Jul 1, 2016	Oct 20, 2024	Apr 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001077415.3:c.575G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001070883.2:p.Cys192Tyr	missense
NM_001031717.4:c.575G>A	NP_001026887.2:p.Cys192Tyr	missense
NM_001374316.1:c.575G>A	NP_001361245.1:p.Cys192Tyr	missense
NM_001374317.1:c.575G>A	NP_001361246.1:p.Cys192Tyr	missense
NM_001374318.1:c.575G>A	NP_001361247.1:p.Cys192Tyr	missense
NM_001374319.1:c.575G>A	NP_001361248.1:p.Cys192Tyr	missense
NM_001374320.1:c.575G>A	NP_001361249.1:p.Cys192Tyr	missense
NM_015513.6:c.575G>A	NP_056328.3:p.Cys192Tyr	missense
NR_164475.1:n.613G>A		non-coding transcript variant
NR_164476.1:n.589G>A		non-coding transcript variant
NR_164477.1:n.963G>A		non-coding transcript variant
NC_000003.12:g.9940964G>A
NC_000003.11:g.9982648G>A
NG_017069.1:g.12124G>A

... more HGVS ... less HGVS

Protein change

C192Y

Other names

Canonical SPDI

NC_000003.12:9940963:G:A

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00011

The Genome Aggregation Database (gnomAD) 0.00014

Exome Aggregation Consortium (ExAC) 0.00018

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023

Links

ClinGen: CA2247733 OMIM: 607170.0006 dbSNP: rs201866563 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.
CRELD1		-	-	GRCh38 GRCh37	161	228

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.
Atrioventricular septal defect, susceptibility to, 2	Uncertain significance (1)	criteria provided, single submitter	Dec 6, 2022	RCV000232440.5
CRELD1-related disorder	Uncertain significance (1)	criteria provided, single submitter	Feb 4, 2020	RCV001255985.2
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Apr 5, 2024	RCV001560495.15
Jeffries-Lakhani neurodevelopmental syndrome	Pathogenic (1)	no assertion criteria provided	Mar 29, 2024	RCV003989107.1

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.
Uncertain significance (Feb 04, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CRELD1-related condition (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Undiagnosed Diseases Network, NIH Study: Undiagnosed Diseases Network (NIH), UDN Accession: SCV001432766.1 First in ClinVar: Sep 19, 2020 Last updated: Sep 19, 2020	Number of individuals with the variant: 1 Clinical Features: Ventricular tachycardia (present) , Vacuolated lymphocytes (present) , Underdeveloped nasolabial fold (present) , Tricuspid regurgitation (present) , Thin vermilion border (present) , Stridor (present) , … (more) Ventricular tachycardia (present) , Vacuolated lymphocytes (present) , Underdeveloped nasolabial fold (present) , Tricuspid regurgitation (present) , Thin vermilion border (present) , Stridor (present) , Strabismus (present) , Status epilepticus (present) , Short philtrum (present) , Seizures (present) , Respiratory failure (present) , Pulmonary edema (present) , Ptosis (present) , Poor head control (present) , Pleural effusion (present) , Plagiocephaly (present) , Pericardial effusion (present) , Oromotor apraxia (present) , Open mouth (present) , Myopathic facies (present) , Muscular hypotonia (present) , Mitral regurgitation (present) , Microcephaly (present) , Metabolic acidosis (present) , Gestational diabetes (present) , Joint hypermobility (present) , Hypoxemia (present) , Hyporeflexia (present) , Hypercapnia (present) , Global developmental delay (present) , Gastrostomy tube feeding in infancy (present) , Gastroparesis (present) , Focal seizures (present) , First degree atrioventricular block (present) , Feeding difficulties in infancy (present) , Failure to thrive in infancy (present) , Drooling (present) , Diarrhea (present) , Delayed gross motor development (present) , Constipation (present) , Congenital malformation of the great arteries (present) , Clonus (present) , Chronic respiratory acidosis (present) , Cerebral atrophy (present) , Cardiomegaly (present) , Cardiogenic shock (present) , Bradycardia (present) , Brachycephaly (present) , Arrhythmia (present) , Abdominal pain (present) (less) Age: 0-9 years Sex: male Ethnicity/Population group: Caucasians Tissue: blood
Uncertain significance (Dec 06, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Atrioventricular septal defect, susceptibility to, 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000285678.6 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024	Comment: In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more) In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 238218). This variant has not been reported in the literature in individuals affected with CRELD1-related conditions. This variant is present in population databases (rs201866563, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 192 of the CRELD1 protein (p.Cys192Tyr). (less)
Pathogenic (Apr 05, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001782921.4 First in ClinVar: Aug 14, 2021 Last updated: Sep 16, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32437232, … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32437232, 37947183) (less)
Uncertain significance (Aug 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004146889.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: CRELD1: PP3 Number of individuals with the variant: 1
Pathogenic (Mar 29, 2024)	no assertion criteria provided Method: literature only	JEFFRIES-LAKHANI NEURODEVELOPMENTAL SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV004805652.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024	Publications: PubMed (1) PubMed: 37947183 Comment on evidence: In 14 patients from 10 unrelated families with Jeffries-Lakhani neurodevelopmental syndrome (JELANS; 620771), Jeffries et al. (2024) identified a c.575G-A transition (c.575G-A, NM_015513.6) in exon … (more) In 14 patients from 10 unrelated families with Jeffries-Lakhani neurodevelopmental syndrome (JELANS; 620771), Jeffries et al. (2024) identified a c.575G-A transition (c.575G-A, NM_015513.6) in exon 5 of the CRELD1 gene, resulting in a cys192-to-tyr (C192Y) substitution at a conserved residue between 2 EGF-like domains. One patient (P17) was homozygous for the mutation. The other 13 patients were compound heterozygous for C192Y and another putatively pathogenic CRELD1 variant. P8 and P9 (family 6), P10 (family 7), P12 (family 9), and P18 (family 14) all carried a 1-bp deletion (c.959delA; 607170.0007) in exon 9, resulting in a frameshift and premature termination (Gln320ArgfsTer25), on the other allele. P5 and P6 (family 4) and P13 and P14 (family 10) carried a 2-bp deletion (c.1128_1129delTG; 607170.0008) in exon 10, resulting in a frameshift and premature termination (Ala377ThrfsTer7), on the other allele. P7 carried a heterozygous c.784T-C transition in exon 7, resulting in a cys262-to-arg substitution (C262R; 607170.0009) at a conserved residue in the calcium-binding EGF domain, on the other allele. P1, P2, and P3 carried different frameshifts on the other allele (c.196dupG and c.254_257del, respectively), and P15 carried a missense variant on the other allele (A391P). The mutations, which were found by whole-exome or whole-genome sequencing, segregated with the disorder in the families. While many of the mutations were present in gnomAD in the heterozygous state at low frequencies (less than 2.97 x 10(-4)), none was homozygous in gnomAD. Studies of patient cells were not performed. Overexpression of the missense variants in X. tropicalis suggested that they variably impaired CRELD1 function. (less)

Comment:

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 238218). This variant has not been reported in the literature in individuals affected with CRELD1-related conditions. This variant is present in population databases (rs201866563, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 192 of the CRELD1 protein (p.Cys192Tyr).

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
Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.	Jeffries L	Genetics in medicine : official journal of the American College of Medical Genetics	2024	PMID: 37947183

Text-mined citations for rs201866563 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001077415.3(CRELD1):c.575G>A (p.Cys192Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201866563 ...