NM_000071.3:c.919G>A

Variant names:

• chr21-43062988-C-T
• rs121964962
• NM_000071.3:c.919G>A

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):​c.919G>A​(p.Gly307Ser) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000543511: Experimental studies have shown that this missense change affects CBS function (PMID:20506325, 22267502)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G307D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 6.85
• Publications: 97 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000543511: Experimental studies have shown that this missense change affects CBS function (PMID: 20506325, 22267502).; SCV000249696: Functional studies found that G307S is associated with significantly decreased CBS enzyme activity compared to wild-type (Hu et al. 1993; Kozich et al. 2010; Hnizda et al. 2012); SCV002821086: PS3:Supporting; SCV000436215: Functional studies have demonstrated that the Gly307 residue is located in the catalytic site of the protein and results in the production of correctly assembled tetramers that are slightly unfolded with a shift towards unfolded intermediates. The catalytic activity of the p.Gly307Ser variant protein is completely abolished (Hu et al. 1993; Hnizda et al. 2012).; SCV000711669: "In vitro functional studies provide evidence that the variant leads to impaired protein function" (Hu 1993, Hnizda 2012, Kozich 2010, Mayfield 2012).; SCV000695310: functional study showed variant with <1% activity in comparison with WT (Kozich_2010).; SCV000738476: "In vitro studies have consistently suggested that this change would abolish enzyme activity, probably by interfering with protein folding (Kim CE et al. Hum. Mol. Genet., 1997 Dec;6:2213-21; Kozich V et al. Hum. Mutat., 2010 Jul;31:809-19; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Hn&iacute;zda A et al. J. Inherit. Metab. Dis., 2012 May;35:469-77)."; SCV004727959: "In experimental studies, the p.Gly307Ser substitution has been shown to greatly impair CBS enzyme activity (Kozich et al. 2010. PubMed ID: 20506325; Mayfield et al. 2012. PubMed ID: 22267502)."
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43062987-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2993386.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, 0.971
• PP5: Variant 21-43062988-C-T is Pathogenic according to our data. Variant chr21-43062988-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.919G>A	p.Gly307Ser	missense	Exon 10 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.919G>A	p.Gly307Ser	missense	Exon 10 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.919G>A	p.Gly307Ser	missense	Exon 10 of 18	NP_001171480.1	P35520-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.919G>A	p.Gly307Ser	missense	Exon 10 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.919G>A	p.Gly307Ser	missense	Exon 10 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.919G>A	p.Gly307Ser	missense	Exon 10 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.000155 AC: 39 AN: 251400 AF XY: 0.000169

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000326

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 46 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 26

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 6

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 36

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome Cov.: 0

Alfa AF: 0.000264 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000654

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Classic homocystinuria (10)
5	-	-	not provided (5)
2	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (2)
1	-	-	CBS-related disorder (1)
1	-	-	Familial thoracic aortic aneurysm and aortic dissection (1)
1	-	-	Homocystinuria (1)
1	-	-	Homocystinuria, pyridoxine-nonresponsive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.95
MPC		1.1
ClinPred		0.73	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.97
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: rs121964962; hg19: chr21-44483098; COSMIC: COSV61446378; COSMIC: COSV61446378;