VCV001915585.3 - ClinVar

NM_000071.3(CBS):c.262C>G (p.Pro88Ala)

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.

(2)

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
Likely pathogenic(1); 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_000071.3(CBS):c.262C>G (p.Pro88Ala)

Variation ID: 1915585 Accession: VCV001915585.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 21q22.3 21: 43068563 (GRCh38) [ NCBI UCSC ] 21: 44488673 (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	Feb 7, 2023	Feb 28, 2024	Sep 13, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000071.3:c.262C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000062.1:p.Pro88Ala	missense
NM_001178008.2:c.262C>G
NM_001178008.3:c.262C>G	NP_001171479.1:p.Pro88Ala	missense
NM_001178009.3:c.262C>G	NP_001171480.1:p.Pro88Ala	missense
NM_001320298.2:c.262C>G	NP_001307227.1:p.Pro88Ala	missense
NC_000021.9:g.43068563G>C
NC_000021.8:g.44488673G>C
NG_008938.1:g.12368C>G
LRG_777:g.12368C>G
LRG_777t1:c.262C>G	LRG_777p1:p.Pro88Ala

... more HGVS ... less HGVS

Protein change

P88A

Other names

Canonical SPDI

NC_000021.9:43068562: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

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.
CBS		-	-	GRCh38 GRCh37	1285	1380

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.
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	Likely pathogenic (1)	criteria provided, single submitter	Sep 13, 2022	RCV002601595.3
Classic homocystinuria	Uncertain significance (1)	criteria provided, single submitter	-	RCV003340518.2

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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Classic homocystinuria (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004047692.1 First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023	Comment: The missense variant c.262C>G (p.Pro88Ala) in CBS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. … (more) The missense variant c.262C>G (p.Pro88Ala) in CBS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Pro88Ala variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Pro at position 88 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Pro88Ala in CBS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). (less) Clinical Features: Global developmental delay (present)
Likely pathogenic (Sep 13, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002949845.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 7762555‚ 22267502 Comment: This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 88 of the CBS protein (p.Pro88Ala). … (more) This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 88 of the CBS protein (p.Pro88Ala). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro88 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7762555, 22267502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 CBS protein function. This variant has not been reported in the literature in individuals affected with CBS-related conditions. This variant is not present in population databases (gnomAD no frequency). (less)

Comment:

The missense variant c.262C>G (p.Pro88Ala) in CBS gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Pro88Ala variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Pro at position 88 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Pro88Ala in CBS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).

Comment:

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 88 of the CBS protein (p.Pro88Ala). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro88 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7762555, 22267502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 CBS protein function. This variant has not been reported in the literature in individuals affected with CBS-related conditions. This variant is not present in population databases (gnomAD no frequency).

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
Surrogate genetics and metabolic profiling for characterization of human disease alleles.	Mayfield JA	Genetics	2012	PMID: 22267502
The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations.	Sebastio G	American journal of human genetics	1995	PMID: 7762555

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000071.3(CBS):c.262C>G (p.Pro88Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...