rs758236584

Variant names:

• chr21-43063958-G-A
• rs758236584
• NM_000071.3:c.770C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):​c.770C>T​(p.Thr257Met) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T257T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 3)
  • Exomes 𝑓: 0.000040 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.70
• Publications: 21 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: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.997
• PP5: Variant 21-43063958-G-A is Pathogenic according to our data. Variant chr21-43063958-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.770C>T	p.Thr257Met	missense_variant	Exon 9 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.770C>T	p.Thr257Met	missense_variant	Exon 9 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 7924 Hom.: 0 Cov.: 3

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000362 AC: 9 AN: 248606 AF XY: 0.0000520

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.0000871

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: 0.000165

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000399 AC: 8 AN: 200730 Hom.: 1 Cov.: 0 AF XY: 0.0000375 AC XY: 4 AN XY: 106574

African (AFR) AF: 0.000283 AC: 2 AN: 7070

American (AMR) AF: 0.000252 AC: 3 AN: 11922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5186

East Asian (EAS) AF: 0.00 AC: 0 AN: 21360

South Asian (SAS) AF: 0.0000361 AC: 1 AN: 27704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 794

European-Non Finnish (NFE) AF: 0.0000192 AC: 2 AN: 104182

Other (OTH) AF: 0.00 AC: 0 AN: 11278

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 7924 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 3534

African (AFR) AF: 0.00 AC: 0 AN: 1750

American (AMR) AF: 0.00 AC: 0 AN: 972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 132

East Asian (EAS) AF: 0.00 AC: 0 AN: 652

South Asian (SAS) AF: 0.00 AC: 0 AN: 316

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 34

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2932

Other (OTH) AF: 0.00 AC: 0 AN: 118

Alfa AF: 0.0000336 Hom.: 0

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:5

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 03, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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. -

Mar 20, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr257Met variant in CBS has been reported in at least 7 individuals with homocystinuria (4 homozygous and 3 compound heterozygous) and segregated with disease in 2 affected individuals from 2 families (Ibrahim 2018, Lee 2005, Li 2018, Sebastio 1995, Urreizti 2006, Zaidi 2012). It has also been identified in 12/279982 total chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 188927). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Mayfield 2012, Yadav 2012, Sebastio 1995, Lee 2005). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive homocystinuria. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2_Supporting, PP1, PP3, PP4. -

Apr 13, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperhomocysteinemia Pathogenic:1

Apr 13, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Pathogenic:1

Jan 11, 2023

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS3,PM1,PM2,PP3,PP5 -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Dec 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 257 of the CBS protein (p.Thr257Met). This variant is present in population databases (rs758236584, gnomAD 0.01%). This missense change has been observed in individual(s) with homocystinuria (PMID: 7762555, 16205833, 16479318, 21517828). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188927). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 7762555, 16205833, 22267502, 22977242). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Oct 16, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #188927; Landrum et al., 2016); In vitro functional studies show a marked decrease in CBS enzymatic activity (Sebastio et al., 1995; Lee et al., 2005; Yadav et al., 2012); 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: 22977242, 21517828, 22267502, 7762555, 29600437, 29508359, 16205833, 23685761, 7967489, 16479318, 31589614) -

Homocystinuria Pathogenic:1

Dec 24, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CBS c.770C>T (p.Thr257Met) results in a non-conservative amino acid change located in the pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 274572 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CBS causing Homocystinuria (4.7e-05 vs 0.003), allowing no conclusion about variant significance. c.770C>T has been reported in the literature in multiple homozygous (Sebastio 1995, Zaidi 2012) and compound heterozygous (e.g. Lee 2005) individuals affected with Homocystinuria. Moreover, the variant was shown to segregate with the disease in one of these families (Sebastio 1995). These data indicate that the variant is very likely to be associated with disease. These publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Sebastio 1995, Lee 2005). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	.;.;.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	1.0	D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.8	H;H;H;H
PhyloP100		8.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.0	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.98
MutPred		0.97		Gain of MoRF binding (P = 0.0819);Gain of MoRF binding (P = 0.0819);Gain of MoRF binding (P = 0.0819);Gain of MoRF binding (P = 0.0819);
MVP		0.94
MPC		1.1
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.99
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758236584; hg19: chr21-44484068;