rs794727835

Variant names:

• chr21-43065499-CCCAGTGCCCGCAGCACGT-C
• rs794727835
• NM_000071.3:c.536_553delACGTGCTGCGGGCACTGG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM4 PP3 PP5

The NM_000071.3(CBS):​c.536_553delACGTGCTGCGGGCACTGG​(p.Asp179_Leu184del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000487 in 410,816 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D179D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 4)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: CBS NM_000071.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 7.79
• Publications: 0 publications found

Genes affected

CBS (HGNC:1550): (cystathionine beta-synthase) The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

CBS Gene-Disease associations (from GenCC):

• classic homocystinuria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000071.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000071.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 21-43065499-CCCAGTGCCCGCAGCACGT-C is Pathogenic according to our data. Variant chr21-43065499-CCCAGTGCCCGCAGCACGT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198388.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.536_553delACGTGCTGCGGGCACTGG	p.Asp179_Leu184del	disruptive_inframe_deletion	Exon 7 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.536_553delACGTGCTGCGGGCACTGG	p.Asp179_Leu184del	disruptive_inframe_deletion	Exon 7 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 4

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 248946 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000487 AC: 2 AN: 410816 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 217014

African (AFR) AF: 0.00 AC: 0 AN: 12904

American (AMR) AF: 0.00 AC: 0 AN: 27198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12876

East Asian (EAS) AF: 0.00 AC: 0 AN: 31152

South Asian (SAS) AF: 0.00 AC: 0 AN: 47628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1768

European-Non Finnish (NFE) AF: 0.00000878 AC: 2 AN: 227916

Other (OTH) AF: 0.00 AC: 0 AN: 23504

GnomAD4 genome Cov.: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Classic homocystinuria Pathogenic:3

Nov 17, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:1 Uncertain:1

Aug 28, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.536_553del18 variant in the CBS gene has been reported in patients with homocystinuria due to CBS deficiency (Kraus et al. 1999; Ruhoy et al. 2014). This variant results in an in-frame deletion of 6 amino acids starting at codon Aspartic acid 179, denoted p.D179_L184. This deletion occurs in a conserved region of the CBS protein and other in-frame deletions in CBS have been reported in the Human Gene Mutation Database (HGMD) in association with homocystinuria due to CBS deficiency (Stenson et al., 2014). The c.536_553del18 variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, we interpret c.536_553del18 to be likely pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Nov 03, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.536_553del18 (p.D179_L184del) alteration is located in exon 7 (coding exon 5) of the CBS gene. This alteration consists of an in-frame deletion of 18 nucleotides between nucleotide positions c.536 and c.553, resulting in the deletion of <NA> residues. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in several individuals with CBS-related homocystinuria and a second variant (Ruhoy, 2014; Gaustadnes, 2002) including one individual with a dislocated lens, mild developmental delay and intellectual disability and a Marfanoid habitus (Gaustadnes, 2002). This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as likely pathogenic. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Nov 20, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.536_553del, results in the deletion of 6 amino acid(s) of the CBS protein (p.Asp179_Leu184del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs794727835, gnomAD 0.003%). This variant has been observed in individual(s) with CBS-deficiency (PMID: 12124992, 24138954; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 198388). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794727835; hg19: chr21-44485609;