21-43060519-A-G

Variant names:

• chr21-43060519-A-G
• rs370163789
• NM_000071.3:c.1067T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP2 BP4_Moderate

The NM_000071.3(CBS):​c.1067T>C​(p.Val356Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V356V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.24
• Publications: 3 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000071.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8318 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to classic homocystinuria.
• BP4: Computational evidence support a benign effect (MetaRNN=0.20725018).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000071.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.1067T>C	p.Val356Ala	missense	Exon 12 of 17	NP_000062.1
	CBS	NM_001178008.3		c.1067T>C	p.Val356Ala	missense	Exon 12 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.1067T>C	p.Val356Ala	missense	Exon 12 of 18	NP_001171480.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.1067T>C	p.Val356Ala	missense	Exon 12 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.1067T>C	p.Val356Ala	missense	Exon 12 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.1067T>C	p.Val356Ala	missense	Exon 12 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00000419 AC: 1 AN: 238714 AF XY: 0.00

Gnomad AFR exome AF: 0.0000656

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 43102 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 22962

African (AFR) AF: 0.00 AC: 0 AN: 2730

American (AMR) AF: 0.00 AC: 0 AN: 3850

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 930

East Asian (EAS) AF: 0.00 AC: 0 AN: 3176

South Asian (SAS) AF: 0.00 AC: 0 AN: 6770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 172

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 22198

Other (OTH) AF: 0.00 AC: 0 AN: 2160

GnomAD4 genome Cov.: 0

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 15, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CBS c.1067T>C (p.Val356Ala) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 238714 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1067T>C in individuals affected with Homocystinuria has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no impact on growth in a S. cerevisiae model (example, Dimster-Denk_2013, Kasak_2019). The following publications have been ascertained in the context of this evaluation (PMID: 23934999, 31301157). ClinVar contains an entry for this variant (Variation ID: 519591). Based on the evidence outlined above, the variant was classified as uncertain significance.

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Dec 21, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V356A variant (also known as c.1067T>C), located in coding exon 10 of the CBS gene, results from a T to C substitution at nucleotide position 1067. The valine at codon 356 is replaced by alanine, an amino acid with similar properties. This variant was included in a study of CBS alterations' B6 cofactor sensitivity and was reported as having no significant differences versus wild-type in yeast culture growth rate at increasing pyridoxine concentrations (Dimster-Denk D et al. G3 (Bethesda), 2013 Oct;3:1619-28). This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Classic homocystinuria Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	0.63
DANN	Benign	0.23
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.8	N
PhyloP100		1.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.45	N
REVEL	Uncertain	0.40
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.72		Gain of ubiquitination at K359 (P = 0.0501)
MVP		0.31
MPC		0.42
ClinPred		0.018	T
GERP RS		-0.12
PromoterAI		0.015	Neutral
Varity_R		0.13
gMVP		0.76
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs370163789; hg19: chr21-44480629;