NM_000032.5:c.1231C>T

Variant names:

• chrX-55014953-G-A
• rs137852305
• NM_000032.5:c.1231C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000032.5(ALAS2):​c.1231C>T​(p.Arg411Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R411H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ALAS2 NM_000032.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.92
• Publications: 9 publications found

Genes affected

ALAS2 (HGNC:397): (5'-aminolevulinate synthase 2) The product of this gene specifies an erythroid-specific mitochondrially located enzyme. The encoded protein catalyzes the first step in the heme biosynthetic pathway. Defects in this gene cause X-linked pyridoxine-responsive sideroblastic anemia. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ALAS2 Gene-Disease associations (from GenCC):

• X-linked erythropoietic protoporphyria

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• X-linked sideroblastic anemia 1

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-55014953-G-A is Pathogenic according to our data. Variant chrX-55014953-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10475.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
ALAS2	NM_000032.5	c.1231C>T	p.Arg411Cys	missense_variant	Exon 9 of 11	ENST00000650242.1	NP_000023.2
ALAS2	NM_001037968.4	c.1192C>T	p.Arg398Cys	missense_variant	Exon 9 of 11		NP_001033057.1
ALAS2	NM_001037967.4	c.1120C>T	p.Arg374Cys	missense_variant	Exon 8 of 10		NP_001033056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALAS2	ENST00000650242.1	c.1231C>T	p.Arg411Cys	missense_variant	Exon 9 of 11		NM_000032.5	ENSP00000497236.1
ALAS2	ENST00000396198.7	c.1192C>T	p.Arg398Cys	missense_variant	Exon 9 of 11	5		ENSP00000379501.3
ALAS2	ENST00000335854.8	c.1120C>T	p.Arg374Cys	missense_variant	Exon 8 of 10	2		ENSP00000337131.4
ALAS2	ENST00000498636.1	c.520C>T	p.Arg174Cys	missense_variant	Exon 4 of 5	3		ENSP00000495662.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 411 of the ALAS2 protein (p.Arg411Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with sideroblastic anemia (PMID: 7592563, 9858242, 32297424). ClinVar contains an entry for this variant (Variation ID: 10475). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALAS2 protein function. Experimental studies have shown that this missense change affects ALAS2 function (PMID: 9858242, 21309041). For these reasons, this variant has been classified as Pathogenic. -

Mar 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ALAS2 c.1231C>T; p.Arg411Cys variant (rs137852305) is reported in the literature in individuals affected with X-linked sideroblastic anemia (Bergmann 2010, Furuyama 1998, Li 2020, Ohba 2013). This variant is also reported in ClinVar (Variation ID: 10475). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Functional analyses of the variant protein show reduced enzymatic activity compared to wild type protein (Ducamp 2011, Furuyama 1998). Computational analyses predict that this variant is deleterious (REVEL: 0.962). Based on available information, this variant is considered to be pathogenic. References: Bergmann AK et al. Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations. Pediatric blood & cancer. 2010 Feb. PMID: 19731322. Ducamp S et al. Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations. Hum Mutat. 2011 Jun. PMID: 21309041. Furuyama K et al. R411C mutation of the ALAS2 gene encodes a pyridoxine-responsive enzyme with low activity. Br J Haematol. 1998 Dec. PMID: 9858242. Li J et al. Novel mutations in the ALAS2 gene from patients with X-linked sideroblastic anemia. Int J Lab Hematol. 2020 Aug. PMID: 32297424. Ohba R et al. Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic syndrome with ring sideroblast (MDS-RS). Annals of Hematology. 2013 PMID: 22983749. -

X-linked sideroblastic anemia 1 Pathogenic:1

Dec 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	.;D;D;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;.;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	.;H;H;.
PhyloP100		9.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.8	D;.;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.90
MutPred		0.93		.;Gain of catalytic residue at M409 (P = 0.0031);Gain of catalytic residue at M409 (P = 0.0031);.;
MVP		0.99
MPC		1.7
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs137852305; hg19: chrX-55041386; COSMIC: COSV58191498; COSMIC: COSV58191498;