21-43060475-C-T

Variant names:

• chr21-43060475-C-T
• rs372010465
• NM_000071.3:c.1111G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):​c.1111G>A​(p.Val371Met) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V371L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.50
• Publications: 7 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 17 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43060475-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2908227.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.962
• PP5: Variant 21-43060475-C-T is Pathogenic according to our data. Variant chr21-43060475-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 212862.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.1111G>A	p.Val371Met	missense_variant	Exon 12 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1111G>A	p.Val371Met	missense_variant	Exon 12 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00000807 AC: 2 AN: 247926 AF XY: 0.00000742

Gnomad AFR exome AF: 0.0000622

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: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000718 AC: 3 AN: 41780 Hom.: 0 Cov.: 0 AF XY: 0.0000890 AC XY: 2 AN XY: 22472

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000432 AC: 1 AN: 2316

American (AMR) AF: 0.00 AC: 0 AN: 3636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 910

East Asian (EAS) AF: 0.00 AC: 0 AN: 2586

South Asian (SAS) AF: 0.00 AC: 0 AN: 7024

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 156

European-Non Finnish (NFE) AF: 0.0000918 AC: 2 AN: 21786

Other (OTH) AF: 0.00 AC: 0 AN: 2176

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0186682), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

Alfa AF: 0.00 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:4

Oct 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2016

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. -

Apr 15, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Oct 02, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V371M variant (also known as c.1111G>A), located in coding exon 10 of the CBS gene, results from a G to A substitution at nucleotide position 1111. The valine at codon 371 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in the compound heterozygous state with other pathogenic or likely pathogenic variants in the CBS gene in four patients reported to have homocystinuria; however, how the phase of the alterations was determined was not indicated (Kluijtmans LA et al. Hum. Genet., 1995 Aug;96:249-50Kluijtmans LA et al. Am. J. Hum. Genet., 1999 Jul;65:59-67; Gaustadnes M et al. Hum. Mutat., 2002 Aug;20:117-26; Oladipo O et al. Clin. Chem., 2010 Nov;56:1665-8). While one assay reported growth similar to wildtype when this variant was expressed in yeast (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23), this variant resulted in a 90% reduction in enzyme activity compared to wildtype when expressed E. coli (Kluijtmans LA et al. Am. J. Hum. Genet., 1999 Jul;65:59-67). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 371 of the CBS protein (p.Val371Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with homocystinuria (PMID: 12124992, 21030686; SOURCE: 10364517). ClinVar contains an entry for this variant (Variation ID: 212862). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 22267502). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Jan 12, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val371Met (GTG>ATG): c.1111 G>A in exon 12 of the CBS gene (NM_000071.2). The Val371Met mutation in the CBS gene has been reported in association with homocystinuria (Kluijtmans L et al., 1995). Kluijtmans et al. reported Val371Met in one individual with homocystinuria, who also harbored another mutation in the CBS gene. Val371Met results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is conserved across species. Mutations in nearby residues (Cys370Tyr, Asp376Asn, Arg379Trp, Arg379Gln) have been reported in association with homocystinuria, further supporting the functional importance of this region of the protein. In summary, Val371Met in the CBS gene is interpreted as a disease-causing mutation. This variant was found in TAAD -

CBS-related disorder Pathogenic:1

Jan 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CBS c.1111G>A variant is predicted to result in the amino acid substitution p.Val371Met. This variant has been reported in multiple patients with homocystinuria, including at least 2 patients with biochemical markers and enzyme testing consistent with CBS deficiency Gaustadnes et al. 2002. PubMed ID: 12124992, Oladipo et al. 2010. PubMed ID: 21030686, Kluijtmans et al. 1999. PubMed ID: 10364517). In vitro functional characterization showed that this variant leads to a >90% reduction in CBS activity (Kluijtmans et al. 1999. PubMed ID: 10364517). However, this variant didn’t affect growth in a yeast model (Mayfield et al. 2012. PubMed ID: 22267502). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Homocystinuria Pathogenic:1

Oct 23, 2023

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.1111G>A (p.Val371Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 247926 control chromosomes. c.1111G>A has been reported in the literature in individuals affected with Homocystinuria in the compound heterozygous state (Kluijtmans_1999, Gaustadnes_2002, Oladipo_2010). These data indicate that the variant is likely to be associated with disease. The variant was reported to lead to reduced levels of enzyme activity in cultured fibroblasts and a transfected e. coli expression system (Kluijtmans_1999). The following publications have been ascertained in the context of this evaluation (PMID: 12124992, 10364517, 21030686). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely 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	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	.;.;.;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.0	H;H;H;H
PhyloP100		7.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.90
MVP		0.95
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		-0.026	Neutral
Varity_R		0.92
gMVP		0.91
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs372010465; hg19: chr21-44480585;