2-44312653-T-C

Variant names:

• chr2-44312653-T-C
• rs121912691
• NM_000341.4:c.1400T>C

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 15P and 2B. PS3 PM5 PP2 PP5_Very_Strong BP4 BS2_Supporting

The NM_000341.4(SLC3A1):​c.1400T>C​(p.Met467Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00316 in 1,613,910 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000731831: Functional studies provide some support that this variant impacts the protein (Chillaron 1997, Bartoccioni 2008, and Calonge 1994)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M467I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: SLC3A1 NM_000341.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:30
• Conservation: PhyloP100: 6.98
• Publications: 73 publications found

Genes affected

SLC3A1 (HGNC:11025): (solute carrier family 3 member 1) This gene encodes a type II membrane glycoprotein which is one of the components of the renal amino acid transporter which transports neutral and basic amino acids in the renal tubule and intestinal tract. Mutations and deletions in this gene are associated with cystinuria. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

SLC3A1 Gene-Disease associations (from GenCC):

• cystinuria

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, PanelApp Australia
• cystinuria type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285542 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000731831: Functional studies provide some support that this variant impacts the protein (Chillaron 1997, Bartoccioni 2008, and Calonge 1994).; SCV000751438: Experimental studies have shown that this missense change affects SLC3A1 function (PMID: 8054986, 9083097, 18332091).; SCV000915917: Calonge et al. (1994) performed functional studies on the p.Met467Thr variant using expression analysis in a Xenopus oocyte system, demonstrating that the variant significantly altered amino acid transport and abolished 80% of normal activity. Chillaron et al. (1997) and Bartoccioni et al. (2008) subsequently demonstrated that the p.Met467Thr variant displays a trafficking defect that maintains an intracellular location rather than being located on the cell surface.; SCV001142318: Functional studies have shown that this missense change affects protein stability, impairs oligomerization and reduces amino acid transport in vitro (PMID: 18332091; 9083097; 8054986).; SCV001157133: Functional analyses of the p.Met467Thr variant protein shows mislocalization leading to decreased transport activity (Bartoccioni 2008, Calonge 1994, Chillaron 1997).; SCV004813554: Multiple studies have shown that this variant impairs normal transport activity of the protein (examples: Calonge_1994, Bartoccioni_2008). PMID: 18332091, 8054986, 17880288, 11748844; SCV005900637: Functional studies demonstrated that the c.1400T>C (p.Met467Thr) variant results in impaired maturation and transport to the plasma membrane (PMID: 9083097, 18332091).; SCV000490814: Published functional studies demonstrate the absence of transport activity in mammalian cells transfected with the M467T variant (Bartoccioni et al., 2008); SCV001550787: "However, functional studies using Xenopus oocytes showed M467T mutants to have reduced transport activity (Bartoccioni_2008_PMID:18332091, Chillarón_1997_PMID:9083097, Calonge_1994_PMID:8054986)."; SCV004949791: Functional studies of this variant, as well as a different variant at the same amino acid (p.M467K), have demonstrated that these alterations lead to delayed transport of the protein and failure to form functional heterotetramers (Calonge, 1994; Chillaron, 1997; Bartoccioni, 2008).; SCV005352256: Functional studies demonstrate the p.Met467Thr variant results in destabilized heterodimers (Bartoccioni et al. 2008. PubMed: 18332091).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-44312654-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3359161.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 25 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: -3.1434 (below the threshold of 3.09). Trascript score misZ: -3.2509 (below the threshold of 3.09). GenCC associations: The gene is linked to cystinuria type A, cystinuria.
• PP5: Variant 2-44312653-T-C is Pathogenic according to our data. Variant chr2-44312653-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 18115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09155038). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000341.4. 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
	SLC3A1	NM_000341.4	MANE Select	c.1400T>C	p.Met467Thr	missense	Exon 8 of 10	NP_000332.2	Q07837-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC3A1	ENST00000260649.11	TSL:1 MANE Select	c.1400T>C	p.Met467Thr	missense	Exon 8 of 10	ENSP00000260649.6	Q07837-1
	SLC3A1	ENST00000409229.7	TSL:1	c.1400T>C	p.Met467Thr	missense	Exon 8 of 9	ENSP00000386620.3	Q07837-6
	SLC3A1	ENST00000409387.5	TSL:1	c.1400T>C	p.Met467Thr	missense	Exon 8 of 10	ENSP00000387308.1	B8ZZK1

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00345

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00250 AC: 627 AN: 251156 AF XY: 0.00266

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00526

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00422

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00325 AC: 4743 AN: 1461594 Hom.: 11 Cov.: 31 AF XY: 0.00316 AC XY: 2295 AN XY: 727120

African (AFR) AF: 0.000568 AC: 19 AN: 33466

American (AMR) AF: 0.000984 AC: 44 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00559 AC: 146 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86250

European-Finnish (FIN) AF: 0.00142 AC: 76 AN: 53418

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.00381 AC: 4241 AN: 1111770

Other (OTH) AF: 0.00295 AC: 178 AN: 60382

GnomAD4 genome AF: 0.00236 AC: 359 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00240 AC XY: 179 AN XY: 74496

African (AFR) AF: 0.000746 AC: 31 AN: 41574

American (AMR) AF: 0.00301 AC: 46 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00346 AC: 235 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00304 Hom.: 2

Bravo AF: 0.00227

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00271 AC: 329

EpiCase AF: 0.00442

EpiControl AF: 0.00379

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
20	-	-	Cystinuria (20)
6	-	-	not provided (6)
1	-	-	Inborn genetic diseases (1)
1	-	-	Kidney disorder (1)
1	-	-	See cases (1)
1	-	-	SLC3A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.092	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.76	N
PhyloP100		7.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.91
Sift	Benign	0.073	T
Sift4G	Benign	0.12	T
Polyphen		0.39	B
Vest4		0.96
MVP		0.93
MPC		0.023
ClinPred		0.016	T
GERP RS		5.8
Varity_R		0.75
gMVP		0.94
Mutation Taster		=3/97	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: rs121912691; hg19: chr2-44539792; COSMIC: COSV105021377; COSMIC: COSV105021377;